S ‐Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction

Abstract

BackgroundMammalian heart regenerative activity is lost before adulthood but increases after cardiac injury. Cardiac repair mechanisms, which involve both endogenous cardiac stem cells (CSCs) and cardiomyocyte cell-cycle reentry, are inadequate to achieve full recovery after myocardial infarction (MI). Mice deficient in S-nitrosoglutathione reductase (GSNOR−⁄−), an enzyme regulating S-nitrosothiol turnover, have preserved cardiac function after MI. Here, we tested the hypothesis that GSNOR activity modulates cardiac cell proliferation in the post-MI adult heart.Methods and ResultsGSNOR−⁄− and C57Bl6/J (wild-type [WT]) mice were subjected to sham operation (n=3 GSNOR−⁄−; n=3 WT) or MI (n=41 GSNOR−⁄−; n=65 WT). Compared with WT,GSNOR−⁄− mice exhibited improved survival, cardiac performance, and architecture after MI, as demonstrated by higher ejection fraction (P<0.05), lower endocardial volumes (P<0.001), and diminished scar size (P<0.05). In addition, cardiomyocytes from post-MI GSNOR−⁄− hearts exhibited faster calcium decay and sarcomeric relaxation times (P<0.001). Immunophenotypic analysis illustrated that post-MI GSNOR−⁄− hearts demonstrated enhanced neovascularization (P<0.001), c-kit+ CSC abundance (P=0.013), and a ≈3-fold increase in proliferation of adult cardiomyocytes and c-kit+/CD45− CSCs (P<0.0001 and P=0.023, respectively) as measured by using 5-bromodeoxyuridine.ConclusionsLoss of GSNOR confers enhanced post-MI cardiac regenerative activity, characterized by enhanced turnover of cardiomyocytes and CSCs. Endogenous denitrosylases exert an inhibitory effect over cardiac repair mechanisms and therefore represents a potential novel therapeutic target.

Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway

“…Given the localization of eNOS to the sarcolemma, it may not induce a direct effect such as S-nitrosylation; alternatively, the signaling may be through the cGMP/PKG pathway. Yet, our results with GSNO and those reported by others [41] suggest that direct S-nitrosylation is associated with accelerated Ca ++ decay. Since models of nitrosoredox imbalance exhibit slower Ca ++ decay [42], and there is evidence that phosphorylation and S-nitrosylation of phospholamban are required for activation of SERCA2a [43], suggests an important role of S-nitrosylation and restoring nitroso-redox balance.…”

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy

“…It has long been known that •NO and S-nitrosation protect the body from cardiovascular disease. Following myocardial infarction ADH5 −/− mice exhibit enhanced cardiac regenerative capabilities as a result of increased cardiac stem cell turnover (Hatzistergos et al, 2015), as well as a reduction in myocardial infarct size and higher coronary vascular density (Lima et al, 2009). Moreover, de-S-nitrosation of cardiac ryanodine receptor 2 (RyR2) in ADH5 −/− mice results in decreased peripheral vascular tone due to calcium “leak” (Beigi et al, 2012).…”

Transnitrosylation: A Factor in Nitric Oxide–Mediated Penile Erection

“…By virtue of GSNOR deficiency, these mice possibly store bioavailable NO in the form of GSNO, which can be donated to thiol groups forming vasoactive S -nitrosothiols [29]. This notion is consistent with the beneficial effect of GSNOR deficiency on cardiac repair [30] and ventricular systolic and diastolic function and tissue oxygenation [31] in a mouse model of myocardial injury. Similarly, pharmacological inhibition of GSNOR reduces vascular resistance and augments blood flow-mediated vasodilation in hypertensive rats [32], while targeted S -nitrosylation reduces neointimal hyperplasia and infarct size in animal models of carotid artery injury [33] and ischemia-reperfusion injury [34].…”