Long recognized as a malodorous and highly toxic gas, recent experimental studies have revealed that hydrogen sulfide (H2S) is produced enzymatically in all mammalian species including man and exerts ...several critical actions to promote cardiovascular homeostasis and health. During the past 15 years, scientists have determined that H2S is produced by 3 endogenous enzymes and exerts powerful effects on endothelial cells, smooth muscle cells, inflammatory cells, mitochondria, endoplasmic reticulum, and nuclear transcription factors. These effects have been reported in multiple organ systems, and the majority of data clearly indicate that H2S produced by the endogenous enzymes exerts cytoprotective actions. Recent preclinical studies investigating cardiovascular diseases have demonstrated that the administration of physiological or pharmacological levels of H2S attenuates myocardial injury, protects blood vessels, limits inflammation, and regulates blood pressure. H2S has emerged as a critical cardiovascular signaling molecule similar to nitric oxide and carbon monoxide with a profound effect on the heart and circulation. Our improved understanding of how H2S elicits protective actions, coupled with the rapid development of novel H2S-releasing agents, has resulted in heightened enthusiasm for the clinical translation of this ephemeral gaseous molecule. This review will examine our current state of knowledge about the actions of H2S within the cardiovascular system with an emphasis on the therapeutic potential and molecular cross talk between H2S, nitric oxide, and carbon monoxide.
Is Cardioprotection Dead? Lefer, David J; Marbán, Eduardo
Circulation,
2017-Jul-04, Letnik:
136, Številka:
1
Journal Article
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For >4 decades, the holy grail in the treatment of acute myocardial infarction has been the mitigation of lethal injury. Despite promising initial results and decades of investigation by the ...cardiology research community, the only treatment with proven efficacy is early reperfusion of the occluded coronary artery. The remarkable record of failure has led us and others to wonder if cardioprotection is dead. The path to translation, like the ascent to Everest, is certainly littered with corpses. We do, however, highlight a therapeutic principle that provides a glimmer of hope: cellular postconditioning. Administration of cardiosphere-derived cells after reperfusion limits infarct size measured acutely, while providing long-term structural and functional benefits. The recognition that cell therapy may be cardioprotective, and not just regenerative, merits further exploration before we abandon the pursuit entirely.
H2S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and ...metabolism of H2S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.
Hydrogen sulfide in biochemistry and medicine Predmore, Benjamin Lee; Lefer, David Joseph; Gojon, Gabriel
Antioxidants & redox signaling,
2012-Jul-01, Letnik:
17, Številka:
1
Journal Article
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An abundance of experimental evidence suggests that hydrogen sulfide (H(2)S) plays a prominent role in physiology and pathophysiology. Many targets exist for H(2)S therapy. The molecular targets of ...H(2)S include proteins, enzymes, transcription factors, and membrane ion channels.
Novel H(2)S precursors are being synthesized and discovered that are capable of releasing H(2)S in a slow and sustained manner. This presents a novel and advantageous approach to H(2)S therapy for treatment of chronic conditions associated with a decline in endogenous H(2)S, such as diabetes and cardiovascular disease.
While H(2)S is cytoprotective at physiological concentrations, it is not universally cytoprotective, as it appears to have pro-apoptotic actions in cancer cells and is well known to be toxic at supraphysiological concentrations. Many of the pleiotropic effects of H(2)S on health are associated with the inhibition of inflammation and upregulation of prosurvival pathways. The powerful anti-inflammatory, cytoprotective, immunomodulating, and trophic effects of H(2)S on the vast majority of normal cells seem to be mediated mainly by its actions as an extremely versatile direct and indirect antioxidant and free radical scavenger. While the overall effects of H(2)S on transformed (i.e., malignant) cells can be characterized as pro-oxidant and pro-apoptotic, they contrast sharply with the cytoprotective effects on most normal cells.
H(2)S has become a molecule of great interest, and several slow-releasing H(2)S prodrugs are currently under development. We believe that additional agents regulating H(2)S bioavailability will be developed during the next 10 years.
Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and ...progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.
For centuries, garlic has been shown to exert substantial medicinal effects and is considered to be one of the best disease-preventative foods. Diet is important in the maintenance of health and ...prevention of many diseases including cardiovascular disease (CVD). Preclinical and clinical evidence has shown that garlic reduces risks associated with CVD by lowering cholesterol, inhibiting platelet aggregation, and lowering blood pressure. In recent years, emerging evidence has shown that hydrogen sulfide (H2S) has cardioprotective and cytoprotective properties. The active metabolite in garlic, allicin, is readily degraded into organic diallyl polysulfides that are potent H2S donors in the presence of thiols. Preclinical studies have shown that enhancement of endogenous H2S has an impact on vascular reactivity. In CVD models, the administration of H2S prevents myocardial injury and dysfunction. It is hypothesized that these beneficial effects of garlic may be mediated by H2S-dependent mechanisms. This review evaluates the current knowledge concerning the cardioprotective effects of garlic-derived diallyl polysulfides.
Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand ...its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models. Listen to this article's corresponding podcast at ajpheart.podbean.com/e/guidelines-for-experimental-models-of-myocardial-ischemia-and-infarction/.
It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart ...growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ∼40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.
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•Murine cardiomyocytes continue to proliferate well after the neonatal period•A proliferative burst in preadolescence establishes the final cardiomyocyte number•Proliferation is initiated by the thyroid hormone/IGF-1/IGF-1-R/Akt pathway•Persistence of cardiomyocyte proliferation improves outcomes after cardiac injury
The heart adjusts to the increased circulatory demand in the postnatal period through a brief intense surge of cardiomyocyte proliferation during preadolescence, initiated by thyroid hormone signaling.
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