Key result
EDH-mediated relaxations were increased in eNOS-KO mice but reduced in n/eNOS-KO mice compared with wild-type, with only n/eNOS-KO mice exhibiting cardiac diastolic dysfunction.
Why the study?
Coronary microvascular dysfunction is associated with cardiac diastolic dysfunction, but the role of endothelium-dependent hyperpolarization in coronary microcirculation and diastolic dysfunction remains to be fully elucidated.
This preclinical study demonstrates that endothelium-dependent hyperpolarization and hydrogen peroxide play crucial roles in maintaining coronary microcirculation and cardiac diastolic function.
Only n/eNOS-KO mice link reduced EDH to diastolic dysfunction; leaves open EDH compensation as a therapeutic target in human HFpEF.
Endothelium-dependent hyperpolarization (EDH) factor is one of endothelium-derived relaxing factors and plays important roles especially in microvessels. We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDH factor produced by all types of nitric oxide synthases (NOSs), including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS. Recent studies have suggested the association between coronary microvascular dysfunction and cardiac diastolic dysfunction. However, the role of EDH in this issue remains to be fully elucidated. We thus examined whether EDH plays an important role in coronary microcirculation and if so, whether endothelial dysfunction, especially impaired EDH, is involved in the pathogenesis of cardiac diastolic dysfunction in mice. Using a Langendorff-perfused heart experiment, we examined the increase in coronary flow in response to bradykinin in the presence of indomethacin and N-nitro-L-arginine (EDH condition) in wild-type, eNOS-knockout (KO), and nNOS/eNOS-double-KO mice. Compared with wild-type mice, EDH-mediated relaxations were increased in eNOS-KO mice but were significantly reduced in n/eNOS-KO mice. Catalase, a specific H2O2 scavenger, markedly inhibited EDH-mediated relaxations in all 3 genotypes, indicating compensatory roles of nNOS-derived H2O2 as an EDH factor in coronary microcirculation. Although both eNOS-KO and n/eNOS-KO mice exhibited similar extents of cardiac morphological changes, only n/eNOS-KO mice exhibited cardiac diastolic dysfunction. The expression of oxidized protein kinase G I-α (PKGIα) in the heart was significantly increased in eNOS-KO mice compared with n/eNOS-KO mice. These results indicate that EDH/H2O2 plays important roles in maintaining coronary microcirculation and cardiac diastolic function through oxidative PKGIα activation.
No takes yet. Share an insight, caveat, or question.
Ikumi et al. (2019) studied Coronary microvascular dysfunction and cardiac diastolic dysfunction. eNOS and nNOS gene knockout vs. Wild-type mice was evaluated on Increase in coronary flow in response to bradykinin (EDH-mediated relaxations) and cardiac diastolic dysfunction. EDH-mediated relaxations were increased in eNOS-KO mice but reduced in n/eNOS-KO mice compared with wild-type, with only n/eNOS-KO mice exhibiting cardiac diastolic dysfunction.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: