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15 pages, 4117 KiB

Open AccessArticle

Aggravation of TGFβ1-Smad Pathway and Autoimmune Myocarditis by Fungicide (Tebuconazole) Exposure

by Ylenia Marino, Alessia Arangia, Ramona D’Amico, Marika Cordaro, Rosalba Siracusa, Daniela Impellizzeri, Enrico Gugliandolo, Roberta Fusco, Salvatore Cuzzocrea and Rosanna Di Paola

Int. J. Mol. Sci. 2023, 24(14), 11510; https://doi.org/10.3390/ijms241411510 - 15 Jul 2023

Cited by 2 | Viewed by 1111

Abstract

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which [...] Read more.

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which is a member of the triazole fungicide family, is utilized to safeguard agricultural crop plants against fungal pathogens. Although TEB poses serious threats to mammal health, the information about how it induces toxic effects through various pathways, particularly in autoimmune diseases, are still limited. Thus, the aim of this paper was to evaluate the effect of TEB exposure in autoimmune myocarditis (AM). To induce AM, rats were immunized with porcine cardiac myosin and exposed to TEB for 21 days. Thereafter, animals were sacrificed, and histological, biochemical, and molecular analyses were performed. TEB exposure increased heart weight, systolic blood pressure and heart rate already augmented by AM. Additionally, it significantly increased creatine phosphokinase heart (CK-MB), creatine phosphokinase (CPK), cardiac troponin T (cTnT), and cardiac troponin I (cTnI), as compared to the control. From the histological perspective, TEB exacerbates the histological damage induced by AM (necrosis, inflammation and cell infiltration) and increased fibrosis and collagen deposition. TEB exposure strongly increased pro-inflammatory cytokines and prooxidant levels (O2⁻, H₂O₂, NO₂⁻, lipid peroxidation) and reduced antioxidant enzyme levels, which were already dysregulated by AM. Additionally, TEB increased NOX-4 expression and the TGFβ1-Smads pathway already activated by AM. Overall, our results showed that TEB exposure strongly aggravated the cardiotoxicity induced by AM. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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13 pages, 2582 KiB

Open AccessCommunication

Atorvastatin Can Modulate DNA Damage Repair in Endothelial Cells Exposed to Mitomycin C

by Maxim Sinitsky, Maxim Asanov, Anna Sinitskaya, Daria Shishkova, Maria Khutornaya, Varvara Minina and Anastasia Ponasenko

Int. J. Mol. Sci. 2023, 24(7), 6783; https://doi.org/10.3390/ijms24076783 - 05 Apr 2023

Cited by 2 | Viewed by 1405

Abstract

HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We studied the cytogenetic damage and the expression of DNA repair genes (DDB1, ERCC4, and ERCC5) [...] Read more.

HMG-CoA reductase inhibitors (statins) are widely used in the therapy of atherosclerosis and have a number of pleiotropic effects, including DNA repair regulation. We studied the cytogenetic damage and the expression of DNA repair genes (DDB1, ERCC4, and ERCC5) in human coronary artery (HCAEC) and internal thoracic artery endothelial cells (HITAEC) in vitro exposed to mitomycin C (MMC) (positive control), MMC and atorvastatin (MMC+Atv), MMC followed by atorvastatin treatment (MMC/Atv) and 0.9% NaCl (negative control). MMC/Atv treated HCAEC were characterized by significantly decreased micronuclei (MN) frequency compared to the MMC+Atv group and increased nucleoplasmic bridges (NPBs) frequency compared to both MMC+Atv treated cells and positive control; DDB1, ERCC4, and ERCC5 genes were upregulated in MMC+Atv and MMC/Atv treated HCAEC in comparison with the positive control. MMC+Atv treated HITAEC were characterized by reduced MN frequency compared to positive control and decreased NPBs frequency in comparison with both the positive control and MMC/Atv group. Nuclear buds (NBUDs) frequency was significantly lower in MMC/Atv treated cells than in the positive control. The DDB1 gene was downregulated in the MMC+Atv group compared to the positive control, and the ERCC5 gene was upregulated in MMC/Atv group compared to both the positive control and MMC+Atv group. We propose that atorvastatin can modulate the DNA damage repair response in primary human endothelial cells exposed to MMC in a cell line- and incubation scheme-dependent manner that can be extremely important for understanding the fundamental aspects of pleoitropic action of atorvastatin and can also be used to correct the therapy of patients with atherosclerosis characterized by a high genotoxic load. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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12 pages, 1277 KiB

Open AccessArticle

Helicobacter Pylori Virulence Factor Cytotoxin-Associated Gene A (CagA) Induces Vascular Calcification in Coronary Artery Smooth Muscle Cells

by Martin O. Sundqvist, Jonatan Wärme, Robin Hofmann, Sven-Christian Pawelzik and Magnus Bäck

Int. J. Mol. Sci. 2023, 24(6), 5392; https://doi.org/10.3390/ijms24065392 - 11 Mar 2023

Cited by 1 | Viewed by 1802

Abstract

Helicobacter pylori (H. pylori) has been associated with cardiovascular diseases. The pro-inflammatory H. pylori virulence factor cytotoxin-associated gene A (CagA) has been detected in serum exosomes of H. pylori-infected subjects and may exert systemic effects throughout the cardiovascular system. The [...] Read more.

Helicobacter pylori (H. pylori) has been associated with cardiovascular diseases. The pro-inflammatory H. pylori virulence factor cytotoxin-associated gene A (CagA) has been detected in serum exosomes of H. pylori-infected subjects and may exert systemic effects throughout the cardiovascular system. The role of H. pylori and CagA in vascular calcification was hitherto unknown. The aim of this study was to determine the vascular effects of CagA through human coronary artery smooth muscle cell (CASMC) osteogenic and pro-inflammatory effector gene expression as well as interleukin 1β secretion and cellular calcification. CagA upregulated bone morphogenic protein 2 (BMP-2) associated with an osteogenic CASMC phenotype switch and induced increased cellular calcification. Furthermore, a pro-inflammatory response was observed. These results support that H. pylori may contribute to vascular calcification through CagA rendering CASMCs osteogenic and inducing calcification. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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16 pages, 16090 KiB

Open AccessArticle

Investigation of the Molecular Mechanisms Underlying the Antiatherogenic Actions of Kaempferol in Human THP-1 Macrophages

by Etimad Huwait, Maha Ayoub and Sajjad Karim

Int. J. Mol. Sci. 2022, 23(13), 7461; https://doi.org/10.3390/ijms23137461 - 05 Jul 2022

Cited by 5 | Viewed by 2295

Abstract

Cardiovascular disease (CVD) is causing high mortality worldwide (World Health Organization-WHO, 2015). Atherosclerosis, the hardening and narrowing of arteries caused by the accumulation of fatty acids and lipids (cholesterol plaques), is a main reason of stroke, myocardial infarction, and angina. Present therapies for [...] Read more.

Cardiovascular disease (CVD) is causing high mortality worldwide (World Health Organization-WHO, 2015). Atherosclerosis, the hardening and narrowing of arteries caused by the accumulation of fatty acids and lipids (cholesterol plaques), is a main reason of stroke, myocardial infarction, and angina. Present therapies for cardiovascular disease basically use statins such as β-Hydroxy β-methylglutaryl-CoA, with <70% efficacy and multiple side effects. An in vitro investigation was conducted to evaluate the impact of kaempferol, a natural medication, in an atherosclerotic cell model. We used cytotoxicity assays, Boyden chamber invasion assays, and quantitative PCR. Affymetrix microarrays were used to profile the entire transcriptome of kaempferol-treated cell lines, and Partek Genomic Suite was used to interpret the results. Kaempferol was not cytotoxic to THP-1 macrophages. In comparison to the control, kaempferol reduced monocyte migration mediated by monocyte chemotactic protein 1 (MCP-1) by 80%. The qPCR results showed a 73.7-fold reduction in MCP-1 and a 2.5-fold reduction in intercellular adhesion molecule 1 (ICAM-1) expression in kaempferol-treated cells. In interferon gamma (IFN-γ) without kaempferol and IFN-γ with kaempferol treated cells, we found 295 and 168 differentially expressed genes (DEGs), respectively. According to DEG pathway analysis, kaempferol exhibits anti-atherosclerosis and anti-inflammatory characteristics. Kaempferol is an effective and safe therapy for atherosclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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Review

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19 pages, 1900 KiB

Open AccessReview

Pathophysiological Effects of Various Interleukins on Primary Cell Types in Common Heart Disease

by Yong Liu, Donghui Zhang and Dan Yin

Int. J. Mol. Sci. 2023, 24(7), 6497; https://doi.org/10.3390/ijms24076497 - 30 Mar 2023

Cited by 3 | Viewed by 2750

Abstract

Myocardial infarction (MI), heart failure, cardiomyopathy, myocarditis, and myocardial ischemia-reperfusion injury (I/R) are the most common heart diseases, yet there is currently no effective therapy due to their complex pathogenesis. Cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), and immune cells are the primary [...] Read more.

Myocardial infarction (MI), heart failure, cardiomyopathy, myocarditis, and myocardial ischemia-reperfusion injury (I/R) are the most common heart diseases, yet there is currently no effective therapy due to their complex pathogenesis. Cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), and immune cells are the primary cell types involved in heart disorders, and, thus, targeting a specific cell type for the treatment of heart disease may be more effective. The same interleukin may have various effects on different kinds of cell types in heart disease, yet the exact role of interleukins and their pathophysiological pathways on primary cell types remain largely unexplored. This review will focus on the pathophysiological effects of various interleukins including the IL-1 family (IL-1, IL-18, IL-33, IL-37), IL-2, IL-4, the IL-6 family (IL-6 and IL-11), IL-8, IL-10, IL-17 on primary cell types in common heart disease, which may contribute to the more precise and effective treatment of heart disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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36 pages, 3773 KiB

Open AccessReview

The Link between Prostanoids and Cardiovascular Diseases

by Livia Beccacece, Paolo Abondio, Carla Bini, Susi Pelotti and Donata Luiselli

Int. J. Mol. Sci. 2023, 24(4), 4193; https://doi.org/10.3390/ijms24044193 - 20 Feb 2023

Cited by 9 | Viewed by 3715

Abstract

Cardiovascular diseases are the leading cause of global deaths, and many risk factors contribute to their pathogenesis. In this context, prostanoids, which derive from arachidonic acid, have attracted attention for their involvement in cardiovascular homeostasis and inflammatory processes. Prostanoids are the target of [...] Read more.

Cardiovascular diseases are the leading cause of global deaths, and many risk factors contribute to their pathogenesis. In this context, prostanoids, which derive from arachidonic acid, have attracted attention for their involvement in cardiovascular homeostasis and inflammatory processes. Prostanoids are the target of several drugs, but it has been shown that some of them increase the risk of thrombosis. Overall, many studies have shown that prostanoids are tightly associated with cardiovascular diseases and that several polymorphisms in genes involved in their synthesis and function increase the risk of developing these pathologies. In this review, we focus on molecular mechanisms linking prostanoids to cardiovascular diseases and we provide an overview of genetic polymorphisms that increase the risk for cardiovascular disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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12 pages, 314 KiB

Open AccessReview

Clinical Evidence on the Potential Beneficial Effects of Probiotics and Prebiotics in Cardiovascular Disease

by Eleni Pavlidou, Aristeidis Fasoulas, Maria Mantzorou and Constantinos Giaginis

Int. J. Mol. Sci. 2022, 23(24), 15898; https://doi.org/10.3390/ijms232415898 - 14 Dec 2022

Cited by 9 | Viewed by 6531

Abstract

The ‘gut microbiome’—the hundreds of trillions of bacteria in the human gastrointestinal tract—serves several functions. The gut microbiome includes all the microorganisms, bacteria, viruses, protozoa, and fungi in the gastrointestinal tract and their genetic material. It helps digest indigestible foods and produces nutrients. [...] Read more.

The ‘gut microbiome’—the hundreds of trillions of bacteria in the human gastrointestinal tract—serves several functions. The gut microbiome includes all the microorganisms, bacteria, viruses, protozoa, and fungi in the gastrointestinal tract and their genetic material. It helps digest indigestible foods and produces nutrients. Through the metabolism of sugars and proteins, it helps the intestinal barrier, the immune system, and metabolism. Some bacteria, such as those in the gut microbiome, cause disease, but others are essential to our health. These “good” microbes protect us from pathogens. Numerous studies have linked an unhealthy gut microbiome to obesity, insulin resistance, depression, and cardiometabolic risk factors. To maximize probiotic benefits in each case, knowledge of probiotic bacterial strains and how to consume them should be increased. This study aims to examine the benefits of probiotic and prebiotic organisms on cardiovascular health, specifically on heart disease, coronary heart disease, stroke, and hypertension. To complete the research, a literature review was conducted by gathering clinical studies and data. The clinical evidence demonstrates the beneficial effect of probiotics and prebiotic microorganisms on the gut microbiome, which has multiple benefits for overall health and especially for cardiovascular diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

26 pages, 1383 KiB

Open AccessReview

Statins in High Cardiovascular Risk Patients: Do Comorbidities and Characteristics Matter?

by Enrica Rossini, Federico Biscetti, Maria Margherita Rando, Elisabetta Nardella, Andrea Leonardo Cecchini, Maria Anna Nicolazzi, Marcello Covino, Antonio Gasbarrini, Massimo Massetti and Andrea Flex

Int. J. Mol. Sci. 2022, 23(16), 9326; https://doi.org/10.3390/ijms23169326 - 18 Aug 2022

Cited by 6 | Viewed by 4832

Abstract

Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins [...] Read more.

Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins are the drug of choice for patients at increased risk of ASCVD and remain one of the most commonly used and effective drugs for reducing LDL cholesterol and the risk of mortality and coronary artery disease in high-risk groups. Unfortunately, doctors tend to under-prescribe or under-dose these drugs, mostly out of fear of side effects. The latest guidelines emphasize that treatment intensity should increase with increasing cardiovascular risk and that the decision to initiate intervention remains a matter of individual consideration and shared decision-making. The purpose of this review was to analyze the indications for initiation or continuation of statin therapy in different categories of patient with high cardiovascular risk, considering their complexity and comorbidities in order to personalize treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Disease 2022)

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