Melatonin protects diabetic heart against ischemia-reperfusion injury, role of membrane receptor-dependent cGMP-PKG activation

Abstract

It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.

Downregulation of microRNA‐155 stimulates sevoflurane‐mediated cardioprotection against myocardial ischemia/reperfusion injury by binding to SIRT1 in mice

“…35 Myocardial I/R results in inflammatory response that leads to further damage to viable myocardial tissues around the infarct, possibly through accelerated cardiomyocyte apoptosis. 6,36 MiR-155 induces pathological cardiomyocyte hypertrophy, and thus repression of endogenous miR-155 expression enables clinical potential to inhibit cardiac hypertrophy and heart failure. 37 Inhibition of miR-155 plays protective roles in ischemic stroke by phosphorylating S6K through the Rheb/mTOR pathway, because increased expression of miR-155 induced elevated cerebral infarct size and cell apoptosis.…”

Curcuminoids: Implication for inflammation and oxidative stress in cardiovascular diseases

“…Curcumin's role as an antioxidant may also be connected to its ability to enhance Nrf2 action. Nrf2 acts as a master regulator of cellular detoxification responses and redox status (Sykiotis et al, ; L. M. Yu et al, ). Under physiological conditions, Nrf2 is generally localized in the cytoplasm, sequestered by its inhibitor Kelch‐like ECH‐associated protein 1 (KEAP1; McMahon, Itoh, Yamamoto, & Hayes, ).…”

“…Curcumin's role as an antioxidant may also be connected to its ability to enhance Nrf2 action. Nrf2 acts as a master regulator of cellular detoxification responses and redox status (Sykiotis et al, 2011;L. M. Yu et al, 2018).…”

Deciphering the roles of FOXO1 in human neoplasms

“…Cardiovascular diseases, cerebrovascular diseases and neoplasms are three major killers among human across the world . Neoplasms cause an enormous burden on society in both developed and developing countries.…”

“…Cardiovascular diseases, cerebrovascular diseases and neoplasms are three major killers among human across the world. [1][2][3][4][5][6] Neoplasms cause an enormous burden on society in both developed and developing countries. The occurrence of neoplasms is increasing because of the growth and aging of the population, as well as increasing exposure to established risk factors.…”