Abstract:Rationale:
Protein S-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared to males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion (I/R) injury. Female hearts also exhibit enhanced S-nitrosoglutathione reductase (GSNO-R) activity, which would typically favor decreased SNO levels as GSNO-R mediates SNO catabolism.
Objective:
Since female hearts exh… Show more
“…We are the first to report the interaction of TMAO with gender in human heart failure myocardium, which has important implications when considering that this microbiome-derived metabolite has been reported widely as a mediator of atherosclerosis, platelet activation, and myocardial infarction [27][28][29]65 ; our data suggests it may be a contributor to the divergence in heart failure outcomes in men and women. An interaction of nitric oxide deficiency with gender in recovery post ischaemia has been reported before in mice 66 , and S-nitrosoglutathione reductase was reported to be a critical sex-dependent mediator of myocardial protein Snitrosylation in mice 67 and murine ex vivo hearts 68 (more active in females); S-nitrosylation is reported as an essential mediator of nitric oxide-dependent cardioprotection 67 . Other work in mice revealed that nitroglycerin-induced calcitonin generelated peptide release is eNOS-dependent, with a greater response in females 69 , and estrogen has been shown to upregulate NOS in neonatal rat cardiomyocytes 70 .…”
Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil genderspecific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.
“…We are the first to report the interaction of TMAO with gender in human heart failure myocardium, which has important implications when considering that this microbiome-derived metabolite has been reported widely as a mediator of atherosclerosis, platelet activation, and myocardial infarction [27][28][29]65 ; our data suggests it may be a contributor to the divergence in heart failure outcomes in men and women. An interaction of nitric oxide deficiency with gender in recovery post ischaemia has been reported before in mice 66 , and S-nitrosoglutathione reductase was reported to be a critical sex-dependent mediator of myocardial protein Snitrosylation in mice 67 and murine ex vivo hearts 68 (more active in females); S-nitrosylation is reported as an essential mediator of nitric oxide-dependent cardioprotection 67 . Other work in mice revealed that nitroglycerin-induced calcitonin generelated peptide release is eNOS-dependent, with a greater response in females 69 , and estrogen has been shown to upregulate NOS in neonatal rat cardiomyocytes 70 .…”
Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil genderspecific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.
“…They are divided into subpopulations that vary structurally and functionally to such an extent that it is possible to observe distinctions even within the very same tissue, as explained by Hollander et al regarding the categorization of cardiac mitochondria into subsarcolemmal (SSM) and interfibrillar types (IFM) [33]. Furthermore, the notion that mitochondrial metabolism is related both to age and sex has been demonstrated empirically several times based on different levels of sensitivity to Ca 2+ [34], mitochondrial permeability transition pore (mPTP) responsiveness [35] and myocardial protection in IRI [36]. These findings should definitely be considered during the development/evaluation of therapeutic approaches to I/R-linked diseases and surgical procedures.…”
Ischemia/reperfusion injury (IRI) permeates a variety of diseases and is a ubiquitous concern in every transplantation proceeding, from whole organs to modest grafts. Given its significance, efforts to evade the damaging effects of both ischemia and reperfusion are abundant in the literature and they consist of several strategies, such as applying pre-ischemic conditioning protocols, improving protection from preservation solutions, thus providing extended cold ischemia time and so on. In this review, we describe many of the latest pharmacological approaches that have been proven effective against IRI, while also revisiting well-established concepts and presenting recent pathophysiological findings in this ever-expanding field. A plethora of promising protocols has emerged in the last few years. They have been showing exciting results regarding protection against IRI by employing drugs that engage several strategies, such as modulating cell-surviving pathways, evading oxidative damage, physically protecting cell membrane integrity, and enhancing cell energetics.
“…Importantly, in a similar study to this one, Casin et al, using another GSNOR inhibitor, N6022, showed similar effects regarding cardioprotection in male mice but not in females [ 47 ]. In fact, in female mice, GSNOR inhibition worsened the damage produced by I–R.…”
The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury.
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