Ang-(1–7) Offers Cytoprotection Against Ischemia–Reperfusion Injury by Restoring Intracellular Calcium Homeostasis

Abstract

Accumulating evidence indicates that angiotensin-(1-7) [Ang-(1-7)] offers protective effects against ischemia-reperfusion (I/R) induced arrhythmias and contractile dysfunction, which are related to disturbances of intracellular calcium homeostasis. However, whether or not Ang-(1-7) regulates intracellular calcium in I/R is not clear. To shed light on this issue, we carried out studies with a cellular model of simulated I/R in isolated rat ventricular myocytes and measured calcium transients using laser scanning confocal microscopy. Our results showed that Ang-(1-7) had no effects on the calcium transient in myocytes superfused with normal solution; however, in myocytes of simulated I/R, Ang-(1-7) significantly attenuated the increased diastolic intracellular Ca during reperfusion, restored the decreased peak Ca of calcium transient during ischemia, and reversed the decreased amplitude of calcium transient throughout the I/R periods. Additionally, Ang-(1-7) significantly suppressed the reactive oxygen species production in I/R, especially during the ischemic phase. These data indicated that Ang-(1-7) affords significant cytoprotective effects through directly improving calcium homeostasis independent of its anti-oxidative action. Most notably, the effects of Ang-(1-7) on intracellular Ca dynamics manifests only in the diseased states, that is, I/R. This unique property suggests that upregulation of Ang-(1-7) expression and/or activation of the Ang-(1-7)/Mas signaling cascade is a highly desirable strategy for the treatment of myocardial impairment induced by I/R.

Icaritin protects against oxidative stress-induced injury in cardiac H9c2 cells via Akt/Nrf2/HO-1 and calcium signalling pathways

“…In addition, icaritin reduced the increase in Ca 2+ release elicited by t-BHP treatment, further suggesting that icaritin may protect mitochondrial integrity by preventing Ca 2+ overload and ROS production. In line with this result, a recent study also demonstrated that angiotensin-(1-7) confers protective effects against ischaemia-reperfusion-induced cardiac dysfunction through inhibiting calcium release and ROS production (Wang et al, 2014). We speculate that t-BHP-mediated Ca 2+ entry into cardiomyocytes involves the accumulation of ROS and the opening of mitochondrial membrane pores.…”

Cellular basis of angiotensin-(1-7)-induced augmentation of left ventricular functional performance in heart failure

“…In addition, the direct effect of Ang-(1–7) on intracellular Ca 2+ mobilization in myocytes is unclear, since previous studies provided conflicting findings. (12;18;19) Furthermore, the ever-emerging body of experimental evidence continues to support that an important subset of cardiovascular actions of Ang-(1–7) is related to its bradykinin (BK) potentiating activity and its facilitation of nitric oxide (NO) release. (6;8;12;20;21) It is reasonable to speculate that the effects of Ang-(1–7) on myocyte may via Ang-(1–7) receptors while be coupled with NO/BK-mediated mechanism.…”

Novel players in cardioprotection: Insulin like growth factor-1, angiotensin-(1–7) and angiotensin-(1–9)

“…Accordingly, the absence of MasR in cardiomyocytes from MasR-KO mice elicits opposite effects over Ca 2+ handling [114]. However, the participation of MasR agonists on Ca 2+ management is still unclear [115,116]. On this regard, as the majority of GPCRs, MasR shows a response depending on the agonist used [117].…”

“…It is widely known that I/R induces arrhythmias and contractile dysfunction in cardiac cells and that Ang-(1-7) has a cardioprotective role. In vitro studies showed that Ang-(1-7) improves Ca 2+ homeostasis in cardiomyocytes subjected to simulated I/R [116]. Regarding to defective electrical coupling in cardiac cells and ischemia-associated arrhythmias, Ang-(1-7) improves cardiomyocyte communication and might improve impulse propagation [124].…”

“…After the identification of MasR as the main receptor for Ang-(1-7) [92], the protective role of Ang-(1-7)/MasR axis has been shown in endothelial dysfunction [119], global ischemia [120], ischemia/reperfusion (I/R) [116], MI [121], cardiac remodeling [122] and HF [123]. It is widely known that I/R induces arrhythmias and contractile dysfunction in cardiac cells and that Ang-(1-7) has a cardioprotective role.…”