Search Results (164)

A sudden increase in ambient oxygen concentration after birth forces the metabolic switch from anaerobic glycolysis to oxidative phosphorylation, which contributes to the rapid decline of cardiomyocyte proliferation. Lactate dehydrogenase A (LDHA), a metabolic enzyme normally localized in the cytoplasm, has been reported to regulate cardiomyocyte proliferation via inducing metabolic reprogramming. Nuclear LDHA has been observed in multiple proliferative cells, whereas the role of LDHA nuclear translocation in cardiomyocyte proliferation remains unresolved. Here we found that the expression of nuclear LDHA was induced both in the infarct area of myocardial infarction (MI) in mice and hypoxic cardiomyocytes in vitro. Mechanically, mild hypoxia prompted metabolic reprogramming which motivated cardiomyocyte proliferation by alleviating reactive oxygen species (ROS), while severe hypoxia coincided with oxidative stress that induced cardiomyocyte cell cycle arrest. Interestingly, LDHA nuclear translocation in cardiomyocytes occurred in response to oxidative stress, and blocking of nuclear LDHA resulted in elevated ROS generation. Collectively, our findings uncover a non-canonical role of nuclear LDHA in maintaining redox balance and resisting cardiomyocyte cell cycle arrest. Full article

Acute myocardial hypoxia/ischemia is associated with abnormal accumulation of myocardial lipids, including dihydroceramides. Here, we characterized how dihydroceramides are remodeled in response to hypoxia and assessed how dihydroceramide remodeling correlates to human cardiac pathophysiology. Hypoxia resulted in a marked accumulation of very-long-chain (VLC)-dihydroceramides in cultured HL-1 cardiomyocytes. In humans, we identified a correlation between the abundance of VLC-dihydroceramides in myocardial biopsies and arrhythmias and heart failure and showed that cardiac expression of CERS2, coding for an enzyme that promotes synthesis of VLC-dihydroceramides, was associated with signaling pathways linked to cardiac arrhythmia and cardiomyopathy. In cultured HL-1 cardiomyocytes, we showed that CerS2 knockdown reduced accumulation of VLC dihydroceramides and altered the expression of mediators regulating Ca²⁺ cycling and electrical conduction. In conclusion, our findings indicate that increased abundance of VLC-dihydroceramides, promoted by increased activity of CerS2 in response to hypoxia, could play a role in cardiac arrhythmias and heart failure. Full article

Poloxamer (P) 188 attenuates myocardial ischemia/reperfusion injury through cell membrane stabilization. Cell–cell interactions between endothelial cells (ECs) and cardiomyocytes (CMs) further protect CMs: co-cultures showed that, at an optimal density, ECs protected CMs against hypoxia/reoxygenation (HR) injury. The mechanism of interaction with P188 still requires exploration. We examined if N(ω)-nitro-L-arginine methyl ester (LNAME), a non-specific nitric oxide (NO) synthase inhibitor, abolishes protection in the presence or absence of P188 and/or ECs. We co-cultured mouse coronary artery ECs in an insert atop mouse CMs plated at confluency on the bottom of a well. Normoxic controls remained in complete media while HR groups were exposed to 24 h hypoxia at 0.01% O₂ in serum- and glucose-free media, followed by 2 h reoxygenation in complete media. P188 (300 μM), LNAME (40 mM), or vehicle were administered upon reoxygenation. ECs at the used lower density did not decrease HR-triggered lactate dehydrogenase release or calcium overload in CMs by themselves. P188 reduced both indicators after HR by 16/18% without and by 22/25% with ECs, respectively. LNAME abrogated CM protection by P188. Neither intervention had an effect under normoxia. Our co-culture data indicates that P188 requires NO, not necessarily of endothelial origin, to elicit CM protection. Full article

Characterized by insufficient blood supply leading to tissue hypoxia and damage, ischemia is the underlying cause of major conditions such as ischemic stroke, myocardial infarction, and peripheral artery disease. Stem cell therapy, as a regenerative strategy, demonstrates significant potential in restoring tissue blood flow and organ function in ischemic environments. This review systematically explores the latest advances in stem cell therapy for ischemic diseases, focusing on different cell types and their mechanisms of action, including direct differentiation, paracrine signaling, immunomodulation, and microenvironment regulation. Furthermore, it highlights innovations in gene editing and bioengineering technologies that enhance cell delivery, targeting, and therapeutic efficacy. Simultaneously, this article discusses the challenges faced, advances in cell tracking and delivery, and future research directions, aiming to provide insights for the development of more effective and personalized treatment strategies Full article

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia. Full article

Background/Objectives: This study aims to investigate the potential etiopathogenesis of HFpEF development and identify possible different phenotypes of HFpEF in patients with chronic obstructive pulmonary disease (COPD) and systemic sclerosis-associated interstitial lung diseases (SS-ILDs). It could help clinicians improve early HFpEF personalized detection and management. Methods: This study included 150 patients with chronic lung diseases (CLDs), such as COPD and SS-ILD, who were outside of exacerbation, had no history of chronic heart failure (CHF), and had a left ventricular ejection fraction (LV EF) of ≥50%. The functional status of the lungs, heart, endothelial dysfunction, and acid–base balance was assessed. The results obtained were compared in groups of patients with CLD depending on the presence or absence of HF with preserved ejection fraction (HFpEF). The diagnosis of HFpEF was established based on the HFA-PEFF Score classification. Nonparametric statistical methods were used. Results: In patients with CLD, indicators such as age, longitudinal size of the right atrium, mid-regional pro-atrial natriuretic peptide (MR-proANP), and highly sensitive cardiac troponin T (hsTnT) were higher than in the group of patients without HFpEF. In patients with COPD and HFpEF, statistically significant changes were found in the volume of the left atrium. In patients with SS-ILD and HFpEF, statistically significant differenceswere found in SBP before and after the 6 min walk test (6MWT), the Borg scale before 6MWT, MR-proANP, and the longitudinal dimension of the right atrium. Conclusions: The results of our study allow us to identify two different mechanisms of HFpEF development: In patients with COPD, the predominant factor in the development of HFpEF was hypoxia, while in patients with SS-ILD, myocardial dysfunction with remodeling developed against the background of secondary pulmonary hypertension, highlighting the importance of phenotype-specific evaluation. These findings suggest potential approaches for personalized risk stratification and the development of targeted management strategies for patients with HFpEF. Full article

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling. Full article

Myocardial oxidative stress increases under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, leading to cellular damage. Inhibition of oxidative stress is involved in the cardioprotective effects of hydrogen sulfide (H₂S) during I/R and diabetes, and H₂S has the potential to protect the heart. However, the mechanism by which H₂S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H₂S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia–reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Treatment with NaHS (100 μM) as an H₂S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH₄) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2′-deoxyguanosine, and dihydrobiopterin (BH₂) concentrations. Additionally, the H₂S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC-1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD, and CAT, and decreased the expression of Keap1, p47phox and NOX4. Therefore, the treatment with the H₂S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and “cardiomyocyte ultrastructure”. Full article

Canine monocytic ehrlichiosis (CME) is a globally prevalent disease transmitted by the tick Rhipicephalus sanguineus and caused by the Gram-negative bacterium Ehrlichia spp. Following an incubation period, the infection is categorized based on the progression of the disease into acute, subclinical, and chronic stages. Besides hematological alterations, the cardiovascular system is significantly impacted by the hemodynamic effects of the disease, as persistent anemia can lead to myocardial hypoxia and the activation of inflammatory processes, potentially causing myocarditis. It is known that in dogs infected with Ehrlichia canis, there is a higher occurrence of arrhythmias and a predominance of sympathetic activity. This study assessed arrhythmogenic parameters, including P wave dispersion (Pd), QT dispersion (QTd), and QT instability, along with heart rate variability (HRV) analysis from 24 h Holter monitoring in naturally infected dogs during the acute phase (n = 10) and chronic phase (n = 10) compared to a control group (n = 10). The Pd and QTd values were higher in the infect group, confirming the arrhythmogenic character. Instability parameters (TI, LTI, and STI) were higher in sick animals, but no worsening was observed in the chronic phase. All HRV metrics in the time domain were higher in the control group, indicating a balanced sympathovagal activity throughout the day in healthy dogs. Additionally, parameters linked to parasympathetic activity (rMSSD and pNN50) were reduced in the sick groups, confirming the dominance of sympathetic activity. These findings indicate a decrease in HRV in sick individuals and reinforce this useful marker for assessing the influence of the autonomic nervous system on the cardiovascular system. In conclusion, CME exhibits arrhythmogenic activity characterized by the deterioration of predictive parameters for ventricular arrhythmias and increased activity of the sympathetic autonomic nervous system in the heart. This is likely secondary to myocarditis, myocardial hypoxia, and structural damage to cardiomyocytes. Full article

Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. Study Design: Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8–12-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1^−/−) mice. WT sham (S) and PHD1^−/−S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1^−/−MI group mices’ heart tissue was used for RNA isolation, then hybridization to a GeneChip™ Mouse Gene 1.0 ST Array as per the manufacturer’s instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. Results: The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1^−/−MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1^−/−MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1α DNA binding activity was higher in PHD1^−/−MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1^−/−MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, p < 0.05) showed 174 differentially regulated genes. Conclusions: In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction. Full article

Background/Objective: Attention should be paid to the introduction of more functional training methods during the second stage of cardiac rehabilitation, which imitate everyday activities to some extent. The main purpose of this research was to analyze the effects of a 22-day training program carried out in normobaric hypoxic conditions corresponding to the altitude of 3000 m a.s.l. in patients after myocardial infarction and to compare it with the same training conducted in normoxic conditions. Material and Methods: This study included 36 patients after myocardial infarction who underwent percutaneous angioplasty with stent implantation. They were examined before and after 2 days of training sessions: day one, spiroergometric exercise test on a mechanical treadmill, blood collection for laboratory tests; day two, echocardiography of the heart. Than patients underwent 22 days of training in hypoxic conditions. At the end of experiment patients had the same examinations as day one and two. Results: Training conducted in hypoxic conditions had a wider impact on spiroergometrical parameters. Significant, beneficial changes were demonstrated in relation to test duration, distance covered, energy expenditure MET, respiratory exchange ratio RER, as well as resting values of systolic and diastolic blood pressure. There were no changes in parameters for morphology, cytokines, and fibrinogen. There were some differences in relation to echocardiography examinations. Conclusions: The conditions in which the rehabilitation training was conducted affect the level of exercise tolerance. The hypoxic conditions in which the training was conducted affected only two hemodynamic parameters: LVESd and e’ septal. Rehabilitation training conducted in various environmental conditions had an impact only on the IL-10 value. Full article

While the beneficial effects of colchicine on inflammation and infarcted myocardium have been documented, its impact on cardiac fibroblast activation in the context of myocardial infarction (MI) remains unknown. This study aimed to investigate the effect of colchicine on the regulation of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and Interleukin-1β (IL-1β) expression in fibroblasts. 3T3 fibroblasts were exposed to 600 μM CoCl₂ for 24 h to simulate hypoxia, with normoxic cells as controls. Colchicine (1 μM) was administered for 24 h. ASC-NLRP3 colocalization and IL-1β expression were evaluated using immunofluorescence and flow cytometry, respectively. Data were analyzed using t-tests and one-way ANOVA with post hoc tests. Hypoxia treatment significantly induced apoptosis-associated speck-like protein containing a CARD (ASC)-NLRP3 colocalization (p < 0.05). Colchicine treatment of hypoxic 3T3 cells reduced ASC-NLRP3 colocalization, although this reduction was not statistically significant. Additionally, IL-1β expression was significantly inhibited in colchicine-treated hypoxic 3T3 cells compared to those treated with placebo (p < 0.05). The findings of this study indicate that colchicine treatment inhibits the activation of the NLRP3 inflammasome by disrupting the colocalization of ASC and NLRP3, thereby reducing IL-1β expression in CoCl₂-treated 3T3 cells. Full article

Microvascular ischemia, especially in the heart and kidneys, is associated with inflammation and metabolic perturbation, resulting in cellular dysfunction and end-organ failure. Heightened production of adenosine from extracellular nucleotides released in response to inflammation results in protective effects, inclusive of adaptations to hypoxia, endothelial cell nitric oxide release with the regulation of vascular tone, and inhibition of platelet aggregation. Purinergic signaling is modulated by ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39, which is the dominant factor dictating vascular metabolism of extracellular ATP to adenosine throughout the cardiovascular tissues. Excess levels of extracellular purine metabolites, however, have been associated with metabolic and cardiovascular diseases. Physiological estrogen signaling is anti-inflammatory with vascular protective effects, but pharmacological replacement use in transgender and postmenopausal individuals is associated with thrombosis and other side effects. Crucially, the loss of this important sex hormone following menopause or with gender reassignment is associated with worsened pro-inflammatory states linked to increased oxidative stress, myocardial fibrosis, and, ultimately, diastolic dysfunction, also known as Yentl syndrome. While there is a growing body of knowledge on distinctive purinergic or estrogen signaling and endothelial health, much less is known about the relationships between the two signaling pathways. Continued studies of the interactions between these pathways will allow further insight into future therapeutic targets to improve the cardiovascular health of aging women without imparting deleterious side effects. Full article

This study was designed to evaluate the protective effects of eleutheroside B (EB) in high-altitude-induced myocardial injury (HAMI) and to unravel the underlying molecular mechanisms. SD rats were used for in vivo experiments. Following pretreatment with EB, the SD rats were exposed to a hypobaric environment within a hypobaric chamber for 48 h. Electrocardiograms, H&E staining, and serum biochemical indices were measured to evaluate the protective effects of EB on HAMI. Immunofluorescence and Western blotting were utilized to detect the expression of associated proteins. In parallel, a hypobaric hypoxic cell incubator was used to establish an in vitro model of hypobaric hypoxia-induced cell injury. The anti-necroptotic effect and its potential underlying mechanisms were investigated and verified in vitro. Exposure to hypobaric hypoxia led to electrocardiogram disorders, pathological changes in myocardial tissue, increased concentrations of BNP and CK-MB, and elevated levels of oxidative stress indicators and inflammatory factors. Additionally, the expression of necroptosis-related proteins was upregulated. Pretreatment with EB effectively ameliorated myocardial injury caused by hypobaric hypoxia, mitigated oxidative stress and inflammation, and suppressed necroptosis. Furthermore, EB facilitated the translocation of Nrf2 into the nucleus. In conclusion, this study provides evidence suggesting that EB may exert a protective effect against HAMI by inhibiting cardiomyocyte necroptosis via the Nrf2/HO-1 signaling pathway. Full article

Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs’ hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies. Full article