Marine-Derived Compounds Applied in Cardiovascular Diseases: Submerged Medicinal Industry

Cardiovascular diseases (CVDs) are among the most impactful illnesses globally. Currently, the available therapeutic option has several side effects, including hypotension, bradycardia, arrhythmia, and alteration in different ion concentrations. Recently, bioactive compounds from natural sources, including plants, microorganisms, and marine creatures, have gained a lot of interest. Marine sources serve as reservoirs for new bioactive metabolites with various pharmacological activities. The marine-derived compound such as omega-3 acid ethyl esters, xyloketal B, asperlin, and saringosterol showed promising results in several CVDs. The present review focuses on marine-derived compounds’ cardioprotective potential for hypertension, ischemic heart disease, myocardial infarction, and atherosclerosis. In addition to therapeutic alternatives, the current use of marine-derived components, the future trajectory, and restrictions are also reviewed.


Introduction
Cardiovascular diseases (CVDs) are one of the most critical conditions affecting human health globally. It includes pulmonary circulation, heart, vascular, and cerebrovascular diseases with higher recurrence and incidence rates [1]. According to 2019 data, CVDs cover 32% with approximately 17.9 million of all deaths around the world. The incidence of CVD-related mortality has grown from 12.1 in 1991 to 18.6 million in 2019 and is expected to increase to 24 million by 2030 [2]. It has been estimated that CVDs will affect approximately 135 million people, with USD 1.1 trillion in costs [3]. Approximately one third of all fatalities worldwide in 2019 were attributable to CVDs, which caused the deaths of 8.9 million women and 9.6 million men. A total of 6.1 million of these fatalities occurred between the ages of 30 and 70. China had the most CVD fatalities, followed by India, the Russian Federation, the United States, and Indonesia [4]. An equal proportion of males and females are affected by CVDs globally, but mortality is higher among women [5]. The goal of the recommendations made by an international group of leaders and professionals in the area is to significantly lower the burden of cardiovascular disease worldwide by 2030 [6]. There are several possible causes of CVDs, such as obesity, smoking, high blood pressure, hyperlipidemia, and diabetes [7]. However, mitochondrial dysfunction is a major factor in CVDs' pathogenesis via regulating ROS generation [8]. Diseases such as diabetes mellitus, COVID-19 [9], and chronic kidney disease (CKD) [10] also cause CVDs via various pathological pathways in both male and female populations around the world [11]. Currently, several synthetic drugs, including plasminogen activators, angiotensin-converting enzyme blockers, angiotensin-2 receptor blockers, calcium channel blockers, β-blockers, diuretics, and surgery, are used to treat CVDs. However, they are associated with severe adverse effects, including time-dependent effects, hypotension, hypersensitivity, bradycardia, arrhythmia, alteration in several ion levels, e.g., potassium and sodium, and surgical complications [12]. Thus, there is a gap in finding new molecular targets and mechanisms to overcome side effects associated with exitance therapy. Marine drugs have minimal toxicity, no multidrug resistance, and no immune system suppression in CVDs' patients [13]. Marine natural drugs are more convenient for CVDs due to their high safety profile, numerous biological activities, and natural origin [14]. Furthermore, they demonstrate a wide range of biological actions against various CVDs, including antioxidant, lipid lowering, anti-inflammatory, thrombin inhibition, anti-coagulation, vasodilation, hypoglycemia inducing, antiplatelet activation, and enzyme and ion channel receptor blocking [15]. Thus, marine-derived natural compounds are novel candidates over synthetic drugs for the minimization of adverse effects in CVDs and associated complications. Marine pharmaceuticals are preferable to other products due to their low toxicity, chemical variety, economic effectiveness, and demonstrated therapeutic promise.

Marine Biodiversity: As Bioactive Reservoirs
The importance of marine natural products (MNPs) in drug discovery, particularly their role in creating current medications, has been well documented [16]. Marine species are the most current source of bioactive natural compounds compared to terrestrial plants and nonmarine microbes. By 2016, 28500 MNPs had been identified, and most had anticancer and cytotoxic properties [17].
The marine environment is a natural habitat for a wide diversity of species with varying physiologies and adaptability to the environment. Out of the more than 33 animal phyla known today, 32 phyla are represented in the marine environment, 15 of which are peculiar to the marine environment [18]. More than 80% of the world's plant and animal species live in the oceans. Marine organisms include sponges, tunicates, fishes, soft corals, nudibranchs, sea hares, opisthobranch, mollusks, echinoderms, bryozoans, prawns, shells, sea slugs, and marine microorganisms are sources of bioactive compounds [19,20]. Marine ecosystems provide a rich reservoir of novel bioactive chemical entities with significant medicinal potential [21]. The diversity of such molecules is distinct, and their development is encouraged by the chemical and physical circumstances of the sea. It is well known that marine species can create bioactive chemicals to protect themselves against unusual environmental circumstances such as high salt, reactive oxygen species, photodynamic damage, and high temperatures [22]. The ancient Greek, Byzantium, and Mediterranean cultures used marine animals for therapeutic reasons. Since marine invertebrates have become so significant in medical practice, much work has been committed to utilizing them. The medicinal or therapeutic properties and how raw materials are handled and delivered were recorded in ancient literature. Several marine invertebrates have been utilized as fresh or dried meat in beverages, liquids, crushed goods, soups, and ointments [23]. Traditional Chinese medicine has also contributed to marine drug research. Local diaries, folk recipes, bibliographies, early prescriptions, and dietary advice have contributed to our comprehensive grasp of marine medicines and other species. All of this information, as well as subsequent discoveries, may be found in the Chinese marine Materia medica [24]. Despite over 250 years of marine research, over 91% of marine creatures still require a complete description. Since the earliest marine animals appeared around 3500 million years ago, adverse conditions fostered the evolution of a diverse range of bioactive chemicals to resist environmental stress [25].
The birth of marine drugs occurred in the 19th century, once biotechnology arose as a science that offered direction to the research of marine medication creation. These marine-derived medications have been utilized to treat various ailments, including cancer, heart disease, diabetes, and neurodegenerative disease [26]. Over the last five decades, evidence has accumulated that marine-based plants and microbes have a greater potential for cancer treatment. For example, cytarabine, eribulin mesylate, brentuximab vedotin, and trabectidine are marine-based drugs used to treat leukemia, metastatic breast cancer, soft tissue sarcoma, and ovarian cancer [21]. Currently, ≥26,680 have been isolated and identified from marine-derived sources, with an average addition of 1000 per year. Due to the specificity of bioactive compounds toward the targets, they are beneficial in cancer therapy targeting cancerous cells [27].

Classification of Marine Drugs
Marine drugs are classified based on their sources and pharmacological actions, compiled in Table 1, Figure 1A,B.

Hypertension
Hypertension is one of the most severe problems among all CVDs, and is responsible for stroke, ischemic heart disease, dementia, chronic kidney disease, and other CVDs [62]. According to 2019 age-standardized prevalence data, 32% of women and 34% of men aged 30-79 worldwide had hypertension [63]. Many marine natural compounds, including bioactive molecules, chito-oligosaccharide derivatives (COS), and phlorotannins, were obtained from marine species and are potential leads for ACE inhibitors and evolved as nutraceutical medicinal compounds for the treatment of hypertension [64,65]. Natural marine ACE inhibitors are being studied as alternatives to synthetic drugs to avoid several serious side effects and hold a significant potential to become new therapeutic options for the treatment of hypertension [66]. Biopeptides or ACE-inhibitory peptides derived from fish proteins are often made under controlled circumstances by proteolyzing marine proteins advanced for the treatment of hypertension [67]. Furthermore, marine red algae Gracilariopsis lemaneiformis have been identified as producing several marine-based new ACE inhibiting peptides, FQIN [M(O)] CILR and TGAPCR, discovered by LC-MS/MS screening in G. lemaneiformis protein hydrolysates. These peptides significantly decreased systolic and diastolic blood pressure (DBP) in the spontaneously hypertensive rat model [68]. In the same direction, Sato M. et al. identified seven peptides: Val-Tyr, Ile-Tyr, Ala-Trp, Phe-Tyr, Val-Trp, Ile-Trp, and Leu-Trp from hydrolysates of wakame (Undaria pinnatifida) brown seaweed using three steps, HPLC and liquid chromatography-mass spectroscopy. Four of seven seaweed-derived peptides (Val-Tyr, Ile-Tyr, Phe-Tyr, and Ile-Trp) significantly reduced systolic blood pressure in spontaneously hypertensive rats at a dose of 1 mg/kg. This offers a possible source of new AEC inhibitors as antihypertensives [69]. In addition, Sun et al. also identified two Phe-Gly-Met-Pro-Leu-Asp-Arg (FGMPLDR; MW 834.41 Da) and Met-Glu-Leu-Val-Leu-Arg (MELVLR; MW 759.43 Da) ACE inhibitory peptides from the protein hydrolysate marine macroalga of Ulva intestinalis. In silico and in vitro molecular docking studies revealed these two peptides have ACE binding and inhibitory activity [70].
One of the most well-known marine-derived compounds is alginate oligosaccharides (AOS) that offer protection against perivascular inflammation, reduction in the vascular luminal area, and hemodynamic alterations of pulmonary hypertension in the rat produced by monocrotaline (MCT) model via downregulating P-selectin [71]. Another study demonstrated that omega-3 Q10, a polyunsaturated fatty acid (n3-PUFA) formulation, appears to be more effective than soybean oil supplementation at reducing diastolic blood pressure and associated symptoms with hypertension in older adults [72]. Moreover, mangrove fungus-isolated xyloketal B showed phenylephrine (Phe)-induced contractions induced hypertension protection by decreasing the systolic and diastolic blood pressure via enhancing endothelial NO release through the Akt/eNOS pathway [51]. In addition, a controlled trial study conducted by Sámano MJ et al. evaluated the combination of Spirulina (Arthrospira) maxima (filamentous, gram-negative cyanobacterium) with angiotensin-converting enzyme (ACE) inhibitors in patients with systemic arterial hypertension (SAH) and accessed its effects on endothelial damage and oxidative stress. Results showed that Spirulina significantly reduced systolic blood pressure, increased anti-oxidant level (glutathione peroxidase activity and oxidized glutathione), and decreased endothelial damage markers (sVCAM-1, sE-selectin, and endothelin-1) [73]. It has other properties such as antiviral, anti-dyslipidemic, and antioxidant [74]. Low molecular mass potassium alginate (L-PA), brown algae, shows an antihypertensive effect on DOCA salt-induced hypertension in rats ( Figure 2) [75]. Overall, data suggested that marine-derived compounds have the potential to cure hypertension, but a detailed mechanistic study is still needed. Moreover, Therapeutic potential of marine drugs in CVDs management has been tubulated in Table 2.

Atherosclerosis
Atherosclerosis is a chronic, inflammatory, progressive cardiovascular disease that results from ongoing blood vessel damage brought on by hyperlipidemia and increased cholesterol levels [93]. Marine-based derived compounds have been effective against atherosclerosis since ancient times. These compounds have advantages over synthetic compounds in atherosclerosis due to greater effectiveness and lower side effects [94]. Marine-derived algal polysaccharides are the active ingredients in products made from marine sources that have a hypolipidemic impact and cure atherosclerosis.
Saringosterol, a phytosterol derived from the edible marine seaweed Sargassum fusiforme, has high and selective liver X receptor (LXR) activity [95]. Yan et. al. reported that saringosterol treatment reduced the burden of atherosclerotic plaques while having no negative effects on the liver of apoE-deficient rats. Saringosterol reduces cholesterol homeostasis disruption, influencing atherosclerosis's progression [79]. However, asperlin is derived from the marine fungus Aspergillus versicolor LZD4403 and possesses antifungal and anti-inflammatory properties. Zhou Y et. al. reported that asperlin has atheroprotective potential in vitro and in vivo. Results indicated that asperlin treatment significantly reduced inflammatory cytokines (iNOS, IL-1β, and TNF-α), increased protective cytokines (IL-10 and IL-4), and reduced aortic dilation and atherosclerosis plaque formation in the aorta [77]. This suggested that the anti-inflammatory properties of asperlin could be beneficial against atherosclerosis. Manzamine A is a naturally occurring alkaloid obtained from the sea sponge Acanthostrongylophora ingens [96]. In atherosclerosis, Eguchi et al. conducted a study where Manzamine A suppressed acyl-CoA: cholesterol acyl-transferase activity in hamster ovary cells. In addition, Manzamine A treatment significantly reduced the serum level of total cholesterol, free cholesterol, LDL-cholesterol, triglyceride, and atherosclerotic lesion formation in apolipoprotein E (apoE)-deficient mice [80]. Astaxanthin is a xanthophyll pigment obtained from microalgae, fungi, complex plants, seafood, and flamingos. As an antioxidant with anti-inflammatory characteristics, it has the potential to be used as a treatment for atherosclerotic cardiovascular disease [97]. Yang Y et. al. demonstrated the hypocholesterolemic effect of astaxanthin via reducing total plasma cholesterol, TG and increased LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl CoA reductase, and sterol regulatory element binding-protein 2 (SREBP-2) and greater mature SREBP-2 protein apoE(-/-) mice ( Figure 3) [81]. In high-fat diet mice, Xyloketal B also protects against atherosclerosis through a strong antioxidant effect [78]. Several marine-derived drugs have been investigated to inhibit thrombo-inflammation in CVDs. Fascaplysin is a Fijian marine sponge derived from the genus Fascaplysinopsis [101], which is a kinase inhibitor with anti-thrombotic properties via inhibiting GPIIb/IIIa activation, platelet aggregation, and thrombus formation [83]. Another cy- Moreover, there are several major causes of atherosclerosis. However, thermo-inflmation plays a crucial role in atherosclerosis pathogenesis via influencing the plague formation. Thrombo-inflammation refers to the complex cascading interaction between the blood coagulation process and inflammation in the pathogenesis of CVDs [98]. The formation of arterial thrombosis is mostly caused by platelet adhesion under high shear stress, which arises in stenotic atherosclerotic arteries [99]. Meanwhile, platelet-activating factor (PAF) is a powerful lipid mediator that acts through PAF/PAF-R pathways and is a key player in inflammation by recruiting neutrophils and activating platelets in the development of atherosclerosis [100].
Several marine-derived drugs have been investigated to inhibit thrombo-inflammation in CVDs. Fascaplysin is a Fijian marine sponge derived from the genus Fascaplysinopsis [101], which is a kinase inhibitor with anti-thrombotic properties via inhibiting GPIIb/IIIa activation, platelet aggregation, and thrombus formation [83]. Another cyclodepsipeptide marine compound Isaridin E derived from the Amphichorda feline (Beauveria feline) fungus [102], demonstrated the dose-dependent inhibition of platelet activation, aggregation, and secretion. However, it does not have any effect against thrombin-or collagen-induced platelet aggregation. Isaridin E also showed an antithrombotic effect without increasing bleeding time in a dose-dependent manner against the FeCl 3 -induced carotid mouse model [84]. F-fucoidan (FD) is a polysaccharide compound derived from the brown alga Laminaria japonica that also shows an antithrombotic effect through shortening the blood lysis time, H2O2 expression stimulation, and H2O2 released after induction of PGI2 production and might be effective in CVDs' patients [103]. The anti-thrombotic and anti-atherosclerotic properties of marine-derived omega 3 polyunsaturated fatty acids (n-3 PUFA) may help to reduce heart failure by lowering the risk of ischemic heart disease. It is known that n-3 PUFA enhances plasminogen activator inhibitor-1 by lowering fibrinogen and decreasing platelet-derived thromboxane A2 (TXA2), which increases platelet aggregation and vasoconstriction [104]. Therefore, So, overall, it seems like marine-based drugs could be used to treat atherosclerosis, but a more detailed mechanistic study is still needed.

Myocardial Infarction (MI)
MI occurs due to the occlusion of the coronary artery, leads to a shortage in oxygen and nutrients, and causes irreversible necrosis and death of cardiomyocytes [105]. It is the major cause of death and disability among other CVDs worldwide [106]. Using marine-derived metal nanoparticles, a novel method for treating thrombus dissolution and myocyte healing in infarcted areas (myocardial infarction) [107]. The anti-myocardial infarction activity of the gold nanoparticles (GNPs) was an innovative method in which cyanobacterial extract, GNP solution, and a combination of both were developed [85]. Omega-3 polyunsaturated fatty acids (PUFA), a marine compound, have shown beneficial benefits on myocardial infarction by reducing MI size in experimental and clinical research ( Figure 3) [104]. Docosahexaenoic acid (DHA) is a long-chain omega-3 PUFA obtained from the marine source that has shown a protective effect against myocardial infarction [87]. An in vivo study of DHA in a rat model showed a protective effect against MI at 5 g/kg [108]. There are few marine-derived compounds in MI that have been investigated until now. Thus, in addition, a more detailed mechanistic study is needed.

Ischemic Heart Disease (IHD)
IHD is an inadequate blood supply of the coronary artery to the myocardium. Endothelial dysfunction is the main involvement in the mechanism of IHD [109]. It is the main cause of morbidity and mortality among all CVDs globally [110]. A 2016 report states it is responsible for 9 million deaths worldwide [111]. Marine-derived drugs are better than synthetic drugs to treat IHD due to their affective action and better results [104]. Histochrome, a sodium salt of echinochrome A, is a marine drug found as a common sea urchin pigment. It is a powerful and biosafe cell-priming agent that prevents cardiac progenitor cells (CPCs) from cellular apoptosis via the downregulation of BCL2-associated X (Bax) cleaved caspase-3, and phosphorylated histone, whereas upregulation of Bcl-xL and B-cell lymphoma 2 (Bcl-2) proteins, utilizing patient-derived human CPCs in treating heart disease [112]. In vitro study of echinochrome A (Ech A), a naturally occurring pigment from sea urchins, showed marine anti-thrombotics, especially sulfated polysaccharides, are relevant due to their distinct modes of action and absence of bleeding. Their distinct modes of action as an antithrombotic are due to the high negative charge that sulfation imparts, which enables them to interact with proteins and molecules involved in vital biological processes such as coagulation [113]. In addition, both polysaccharides Enteromorpha prolifera polysaccharides (EPPs), produced from green algae, and fucoidan, extracted from brown algae, have anti-oxidant, lipid-lowering, and antiangiogenic properties [114]. Alginate (ALG), mostly derived from brown seaweed, can lower TC, TG, and LDL-C serum levels and upregulate HDL-C concentrations, making it an effective treatment for coronary artery disease [15].

Cardiac Stroke
Cardiac stroke is the most severe complication of CVDs, causing sudden death. CVDs are mostly caused by cardiac arrest or stroke in individuals with elevated blood pressure, high cholesterol, obesity, increased blood glucose levels, and weight gain [115]. Natural compounds derived from marine sources have already been regarded as lead molecules for treating CVDs and cardiac arrest due to their varied chemical compositions and pharmacological characteristics [116]. A carotenoid molecule called fucoxanthin, obtained from brown algae, prevents lipids' oxidation and buildup [117]. Fucoxanthin protects against cardiac stroke by regulating metabolic syndrome [118]. Another carotenoid, astaxanthin, showed a positive effect in cardiac stroke via the modulating number of biological processes, including the reduction in inflammation, augmentation of oxidative stress, enhancement of antioxidants, and the modification of lipid and glucose concentrations via suppressing TLR4/NF-κB/ROS signaling pathway [119]. A new type of unique structure called Xyloketal B contains a marine component derived from Xylaria species. Xyloketal B can benefit cardiac stroke due to its protective effect in the two-clip stroke-prone hypertensive model [120].

Cardiac Arrhythmia
Cardiac arrhythmias account for 10%-15% of fatalities, making them a substantial reason for morbidity and mortality worldwide [121]. Tetrodotoxin (TTX) is a marine compound obtained from the actinomycetes of marine sediments and has a beneficial effect on cardiac arrhythmia. It is also known as the puffer fish toxin that prevents sodium channels in excitable neurons [122]. It has also shown an antiarrhythmic effect in combinatorial therapy with lidocaine [123].

Cardiac Dysfunction
Chronic cardiac dysfunction is caused by contractility overload on the heart myocardium. Different etiologies may favor existing compensatory mechanisms such as excentric (dilatation) and concentric hypertrophy. Chronic left ventricular dysfunction is the most prevalent complication of MI. Chronic cardiac dysfunction worsens left ventricular ejection fraction and stroke volume as dilatation progresses, eventually leading to heart failure [127]. Retinoid receptors play a crucial role in several diseases, including diabetes [128], cancer [129], and CVDs [130]. A research study reported that the retinoid receptor is essential for heart function. Moreover, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice showed significant diastolic dysfunction, increased intracellular ROS, NOX2 (NADPH oxidase 2), NOX4 and decreased antioxidant level (SOD1 and SOD2). This effect is reversed by overexpression of retinoid receptors [131]. In addition, Guleria RS et al. also demonstrated that retinoid receptors play a role in diabetic-induced cardiomyopathy [132]. In the same way, zeaxanthin heneicosylate (ZH) extracted from microalgae Dunaliella salina significantly reduced plasma biochemical alteration (AST, ALT, urea, and creatinine level), pro-inflammatory level (IL-6, NF-κB, and iNOS), antioxidant level (SOD), and histological changes in D-galactose-induced cardiac dysfunction rats through stimulating the retinoid receptors [92]. There are only a few studies on cardiac dysfunction; thus, detailed mechanistic studies are needed.

Heart Valve Disease or Valvular Heart Disease
Valvular heart disease (VHD) is a cluster of frequent cardiovascular disorders that account for 10-20% of all cardiac surgical operations in the United States. Heart valve problems include regurgitation (valve flaps do not close properly), stenosis (narrowed valve opening), and atresia (valve does not have a proper opening). Fucoxanthin is a marine carotenoid obtained from the seaweed microalgae Phaeodactylum tricornutum and possesses antioxidant and anti-inflammatory properties [133]. A report by Chiang et al. demonstrated the protective potential of heart valves in heart valve interstitial cells and dogs. Results showed that fucoxanthin treatment significantly reduced H 2 O 2 -induced ROS level, DNA damage, cell survival, and protein-related apoptosis and calcification expression via modulating the Akt/ERK pathway. In addition, long-term (0.5 to 2 years) supplementation to the dog also improved the left atrium to aortic (LA/AO) dimension ratio and E/e value (indicate mitral valve inflow, mitral valve leakage, and left ventricular diastolic dysfunction) [91]. This suggests that marine-derived compounds hold a diverse therapeutic potential. In addition, marine drugs which hold biological effects in CVDs tubulated in Table 3.

Minerals
Na, K, Mg, P, I, Zn, and Fe

Microalgae (Chlorococcum humicola and Chlorella vulgaris)
Used for the prevention and treatment of CVDs. [137,138] Na + /K + ratio, Mg Controls blood pressure, prevent metabolic syndrome and atherosclerosis.

NaCl
Increases arterial constriction and peripheral vascular resistance, increased blood pressure.

K +
Decreases the blood pressure, preventing problems associated with high blood pressure.

Clinical Trial Studies of Marine-Derived Drugs in CVDs
Several marine-derived drugs, such as astaxanthin, alginate, eicosapentaenoic acid, etc., have been approved for clinical trial studies in various CVDs. These are effective when used with CVDs patients in clinical trial studies. However, more studies are required to collect data to prove that marine drugs provide a better therapy for CVDs. All the clinical studies on marine-derived drugs for CVDs are compiled in Table 4.

Marine Lipid Bioactive Compounds with Potent Cardio-Protective Properties
Omega-3 polyunsaturated fatty acids (PUFA), carotenoids, lipid vitamins, and polar lipid bioactives from fish sources have been shown to have potent biological effects against inflammation and CVDs [157]. Fish is a good source of bio-functional marine polar lipids (PL), rich in n-3 PUFA, and have powerful antithrombotic, anti-inflammatory, and cardio-protective properties. The amphiphilic features of bioactive fish PL, such as several phospholipids and glycolipids bearing n-3 PUFA in their structure, resulted in a significant increase in the bioavailability of n-3 PUFA content [157]. It has been demonstrated that n-3 PUFA-rich fish lowers the incidence of inflammation-related CVDs. Additionally, it has anti-inflammatory and anti-thrombotic characteristics and transports n-3 PUFA to different bodily organs more effectively than triglycerides [158]. In addition to n-3 PUFA, other fishlipid bioactive nutrients such as fish carotenoids, lipid vitamins A, D, and E, and polar fish lipids (glycolipids and phospholipids) have also shown anti-thrombotic, anti-inflammatory, and antioxidant, cardioprotective effects and reduced CVD risk [158,159]. Polar lipid fractions of sea bass (Dicentrarchus labrax) and gilthead sea bream (Sparus aurata) treated with fish feed enhanced with olive pomace showed powerful antithrombotic properties [160]. The cold-water marine fish cod (Gadus morhua) is a major source of fat-soluble vitamins, EPA and DHA, and high-quality protein. Cod is a lean fish that maintains its fat reserves in the liver as triacylglycerols. It has been reported to possess cardioprotective effects against atherosclerosis and platelet aggregation [161]. Sardines (Sardina pilchardus) are a significant Mediterranean commercial fish that reserves fats in the tissue as triacylglycerols. Sardines have shown a potent cardioprotective effect against platelet aggregation or PAF-induced platelet aggregation [162]. Microalgae are abundant sources of bioactive lipids, including polar lipids and omega-3 and -6 PUFA, which have strong anti-inflammatory properties in CVDs [163].
It has been shown that dietary polar lipids of marine origin can either directly inhibit PAF-binding on a particular cell membrane receptor for PAF or indirectly influence the phospholipid microenvironment in those membranes. These lipids could also prevent PAF production, bringing blood PAF levels to homeostatic levels, which has several anti-inflammatory and anti-atherogenic health effects for cardiovascular [159]. Spirulinaextracted lipid substances, including lipid extracts, phycocyanin protein, phycocyanobilin (PCB), polysaccharides (PS), and bioactive lipid fractions have shown strong cardioprotective effects such as antithrombotic and anti-PAF in washed rabbit platelets stimulated by PAF and thrombin [164]. Gilthead sea bream (Sparus aurata) polar lipids have shown an antiatherosclerotic effect via modulation of PAF metabolism and decreasing activity and levels of PAF in the blood [165]. Phosphatidylcholine (PC) is the most predominant phospholipid (PL) found in marine sources such as mackerel, rainbow trout, tuna, and salmon, followed by phosphatidylethanolamine (PE). Krill (Euphausia superba) oil (KO), a prominent source of marine PLs, show a protective effect on heart failure by reducing heart remodeling [166]. KO increases the amount of n-3 PUFA in the myocardial tissue and reduces the risk of left ventricular (LV) remodeling when taken before myocardial infarction (MI) induction [167]. It also shows a cardioprotective effect by improving blood lipids in dyslipidemia [166]. Marine carotenoids are important bioactive substances with physiological effects connected to the protection of chronic illnesses such as CVDs. These chronic illnesses, including CVDs, have been caused by oxidative stress and inflammation [168]. The dietary supplement, astaxanthin, a xanthophyll carotenoid, is an effective anti-inflammatory and antioxidant in the CVD model. Astaxanthin has been used in human clinical research to evaluate its bioavailability, safety, and clinical features related to oxidative stress and inflammation in CVDs, and no negative consequences were found [118].
Vitamins A and E are abundant in shark liver oil and possess important bio-functionalities, cardio-protective, and antioxidant effects. Their antioxidant effects protect the body against free radicals [157]. Vitamin D and its derivatives, mainly paricalcitol, have shown powerful anti-thrombotic and anti-inflammatory effects against thrombotic PAF and inflammatoryrelated pathways [169]. Vitamin D insufficiency has been related to greater mortality and CVD incidence via several mechanisms, including the activation of the renin-angiotensinaldosterone system, oxidative stress, altered inflammatory pathways, and aberrant nitric oxide regulation [170]. Vitamin E has anti-inflammatory, anti-thrombotic, and antioxidant properties. Its antioxidant properties lower the incidence of CVDs by preventing LDL oxidation [157]. Vitamin E or fish oil was proven to reduce atherosclerosis in rabbits with high cholesterol [82]. Fish oil and n-3 PUFA have been adversely linked to higher levels of LDL cholesterol as well as a possible increase in LDL oxidizability owing to unfavorable lipid changes, overcome by vitamin E co-supplementation, which promotes anti-atherogenic lipid modifications and overall cardiovascular protection, including elevated HDL(2)cholesterol levels, lowered postprandial lipemia, decreased triacylglycerol-rich lipoprotein levels, and lowered remnant levels [171].

Potential Effect of Marine Drug Targeting ROS in CVDs
Reactive oxygen species (ROS) have been generated in terms of H 2 O 2 , hydroxyl radicals, and superoxide anions (O 2 − ) during numerous cascades of cellular processes, including mitochondria respiration. It is also involved in various biological processes, including regulating cellular homeostasis and cell signaling [112]. Researchers have already even reported a significant positive correlation between increased ROS levels and the severity of CVDs [172]. ROS have been implicated in cellular damage, apoptosis, and necrosis, as well as the direct oxidizing effect on several macromolecules such as DNA, RNA, and proteins during CVDs pathogenesis [173]. Moreover, decreased in endothelial nitric oxide synthase leads to decreased in nitric oxide (NO) production, which consequences in an increase in ROS that has been linked to endothelial damage by its interaction with other molecules to produce peroxynitrite radical in hypertension [174]. In addition, patients with systemic arterial hypertension have shown higher ROS levels and reduced NO availability [73]. Several marine drugs, including astaxanthin, fucoidan, fucoxanthin, xyloketal B, histochrome, and spirulina maxima, show potential effects via targeting ROS in CVDs. The antioxidant activity of astaxanthin has been proven in in vivo and in vitro studies via scavenging superoxide, hydroxyl radicals, and hydrogen peroxide and protection from lipid peroxidation [134]. Astaxanthin has shown antioxidant activity through inhibition of ROS generation and is effective against CVDs. A study on rabbits confirmed that it decreased non-protein thiol levels and lipid peroxidation by increasing CAT, SOD, and thioredoxin activity and inhibited ROS generation in the aortic valve [175].
Fucoidan has shown an anti-atherosclerotic effect by triggering various signaling pathways that control lipid metabolism, inhibit inflammation, and reduce oxidative stress. An in vivo study revealed that fucoidan treatment shows a preventive effect against atherosclerosis through the reduction in ROS generation and the expression of ROS generation-related proteins such as endothelial nitric oxide synthase, superoxide dismutase 1, and NADPH oxidase subunit 2/4 in the aorta of LDLR-/-mice. Fucoidan also partially recovers the lipid peroxidation and antioxidant defense system in a mouse model of alimentary hyperlipidemia [176]. Fucoxanthin is another marine drug with a powerful antioxidant effect by inhibiting ROS generation in heart valve cells. In an in vivo study on rats, fucoxanthin has shown a protective effect against H 2 O 2 -induced ROS generation through decreasing oxidative stress, promoting better cell survival, and preventing DNA damage [91]. Xyloketal B has also shown potent antioxidant activity in atherosclerotic disease through scavenging DPPH free radicals and inhibiting ROS generation induced by oxidized low-density lipoprotein (LDL). It might preserve nitric oxide bioavailability in the existence of higher ROS. It has also shown antioxidant activity in the zebrafish model and vascular endothelial cells by heme oxygenase-1 (HO-1) induction [78]. Histochrome is a bio-safe and potent agent that shows a cardioprotective effect against ROS generation or oxidative stress in human cardiac progenitor cells [112]. In the clinical trial study, Spirulina maxima showed a cardioprotective effect against systemic arterial hypertension after decreasing oxidative stress and endothelial damage [73].

Future Prospectus
CVDs are the leading cause of death, affecting millions of people worldwide [177]. Various drugs have been approved to treat CVDs, including antithrombotic agents, betablockers, diuretics, calcium channel blockers, lipid-lowering drugs, and renin-angiotensin system (RAS)-acting agents [178]. Several other new synthetics and natural herbal drugs have been recently discovered to treat CVDs globally. However, CVDs are not completely cured or eradicated by these drugs, and cases are still increasing at a high rate globally. Researchers are continuously exploring novel targets and agents that can reduce the burden of CVDs. Marine-derived drugs are emerging therapeutics in the recent era [179,180]. Experiments and investigations have indicated several marine natural products that are effective for CVDs with minimum adverse effects. Marine drugs can be used in severe conditions for multiple complications such as hypertension, atherosclerosis, myocardial infarction, etc. These drugs may decrease the severe chest pain of anginal pectoris and some other CVDs complications. In the present review, we have emphasized different marine-derived compounds such as asperlin, saringosterol, astaxanthin, manzamine A, xyloketal B, docosahexaenoic acid, echinochrome A, tetrodotoxin, botulinum toxin, zeaxanthin heneicosylate, and fucoxanthin for various CVDs. All of these marine-derived compounds have shown very encouraging results in the in vitro and in vivo studies. Moreover, thousands of marine-derived compounds are added every year to the library of marine compounds. Those compounds need to be explored for their therapeutics in CVDs. A nano-formulation-based approach must also be developed to delivered marine-based compound and are the particular target of interest to avoid side effects. Researchers may directly utilize marine-derived compounds as initial leads for the development of new medications that are more specialized than the original molecule. Based on this, it appears that marine natural products could represent a promising "library" of natural compounds for developing new therapies as adjuvants to gold standard therapies, enhancing the efficacy of conventional drugs, and exerting synergistic or additive positive effects for cardiovascular diseases.

Conclusions
Several synthetic drugs are those most often used today in pharmaceutical corporations. Pharmaceutical corporations have given up on bioactive chemical research for many years in favor of developing and manufacturing synthetic molecules. However, research into natural substances has resumed since the early 2000s and has a place within biomedical investigations. The superior biocompatibility of natural chemicals compared to manufactured pharmaceutical products, without discounting the significant variety of these molecules and their effects, are one of the primary drivers for this return to natural medicines. Marine chemicals and their derivatives have grown in pharmaceutical and medical research during the last 10 years. Unquestionably, one of the reasons is the abundance of available molecules and secondary metabolites, as well as their diversity due to the many unfavorable habitats of the seas and the virtually endless variety of creatures that inhabit them. Antioxidant and anti-inflammatory characteristics, particularly useful for treating cardiovascular disorders, are among the many pharmacological activities on which the research is focused. This review has discussed the therapeutic potential of these marine-derived compounds for CVDs with underlying mechanisms.

Conflicts of Interest:
The authors declare no conflict of interest.