Calcium Sensing Receptor-Related Pathway Contributes to Cardiac Injury and the Mechanism of Astragaloside IV on Cardioprotection

Abstract

Activation of calcium sensing receptor (CaSR) contributes to cardiac injury, but the underlying mechanism has not yet been examined. Astragaloside IV (AsIV) was previously reported to exhibit protective effects against various myocardial injuries. The aim of the present study was to investigate the underlying mechanism of CaSR in cardiac hypertrophy and apoptosis and to evaluate whether the protective effect of AsIV against myocardial injury is associated with CaSR and its related signaling pathway. In vivo and in vitro myocardial injury was induced by isoproterenol (Iso) or GdCl3 (a CaSR agonist) in rats and heart H9C2 cells. Cardiac cell hypertrophy, apoptosis, function, Mitochondrial Membrane Potential (MMP), mitochondrial ultrastructure, and [Ca2+]i, as well as the protein expression of CaSR, calcium/calmodulin-dependent protein kinase II (CaMKII), calcineurin (CaN), sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a), and the inositol 1,4,5-trisphosphate receptor (IP3R), were measured in vivo and/or in vitro. The results showed that AsIV attenuated cardiac hypertrophy and apoptosis and attenuated impairments in cardiac function, mitochondrial structure, and MMP induced by Iso or GdCl3 in rat myocardial tissue and H9C2 cells. Importantly, AsIV treatment inhibited the enhancement of [Ca2+]i and CaSR expression induced by Iso or GdCl3, an effect similar to that of the CaSR antagonist NPS2143. In addition, AsIV treatment repressed CaSR, CaMKII, and CaN activation and inhibited NFAT-3 nuclear translocation. Mechanistic analysis using lentivirus infection showed that CaSR overexpression activated the CaMKII and CaN signaling pathways and that this response was enhanced by Iso. The results suggested that CaSR-mediated changes in [Ca2+]i and CaMKII and CaN signaling pathways contribute to cardiac hypertrophy and apoptosis and are involved in the protective effect of astragaloside IV against cardiac injury.

Silencing of circHIPK3 Inhibits Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction by Sponging miR-185-3p

“…[37][38][39] Moreover, the expression level of CaSR was markedly increased in cardiac hypertrophy, which has been confirmed in our study. 40 In conclusion, using in vitro and in vivo hypertrophy models we have shown that circHIPK3 was up-regulated in pressure-overload induced cardiomyocytes and inhibition of circHIPK3 exerts a protective role against cardiac hypertrophy through sponging of a miR-185-3p. Furthermore, it was shown that miR-185-3p in turn targets the calcium sensing receptor (CaSR) gene in cardiomyocytes and that miR-185-3p knockdown or CaSR over-expression can reverse the effect of circHIPK3.…”

“… 37–39 Moreover, the expression level of CaSR was markedly increased in cardiac hypertrophy, which has been confirmed in our study. 40 …”

Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health

“…Apoptosis and hypertrophy have been linked to the calcium homeostasis and CaSR in the vasculature. For example, CaSR activation leads to the activation of pathways that are calcium ion dependent, such as Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and calcineurin pathways [ 46 ], which are known to induce apoptosis and hypertrophy of cardiac myocytes. Furthermore, angiotensin II (AngII) has been observed to be involved in CaSR induced cardiac fibrosis in-vitro [ 47 ].…”

Astragaloside IV alleviates myocardial damage induced by type 2 diabetes via improving energy metabolism

“…The number of apoptotic and necrotic cardiomyocytes began to increase. When the normal physiological structure was destroyed to a certain extent, compensatory adjustment can no longer compensate for myocardial damage, ultimately leading to heart failure (37).…”