Ischemic postconditioning and pinacidil suppress calcium overload in anoxia-reoxygenation cardiomyocytes via down-regulation of the calcium-sensing receptor

Abstract

Ischemic postconditioning (IPC) and ATP sensitive potassium channel (KATP) agonists (e.g. pinacidil and diazoxide) postconditioning are effective methods to defeat myocardial ischemia-reperfusion (I/R) injury, but their specific mechanisms of reducing I/R injury are not fully understood. We observed an intracellular free calcium ([Ca2+]i) overload in Anoxia/reoxygenation (A/R) cardiomyocytes, which can be reversed by KATP agonists diazoxide or pinacidil. The calcium-sensing receptor (CaSR) regulates intracellular calcium homeostasis. CaSR was reported to be involved in the I/R-induced apoptosis in rat cardiomyocytes. We therefore hypothesize that IPC and pinacidil postconditioning (PPC) reduce calcium overload in I/R cardiomyocytes by the down-regulation of CaSR. A/R model was established with adult rat caridomyocyte. mRNA and protein expression of CaSR were detected, IPC, PPC and KATP’s effects on [Ca2+]i concentration was assayed too. IPC and PPC ameliorated A/R insult induced [Ca2+]i overload in cardiomyocytes. In addition, they down-regulated the mRNA and protein level of CaSR as we expected. CaSR agonist spermine and KATP blocker glibenclamide offset IPC’s effects on CaSR expression and [Ca2+]i modulation. Our data indicate that CaSR down-regulation contributes to the mitigation of calcium overload in A/R cardiomyocytes, which may partially represents IPC and KATP’s myocardial protective mechanism under I/R circumstances.

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

“…In 2012, in a work performed in vivo and on isolated adult rat cardiomyocytes subjected to a hypoxia post-conditioning protocol, the authors suggested that the pro-apoptotic action of CaR exerted via ER stress activation was counteracted during post-conditioning by a reduction of CaR protein expression [ 221 ]. Very recently, Zhang and colleagues confirmed that ischemic post-conditioning and KATP channel agonists diazoxide and pinacidil exert a protective effect against ischemia/reperfusion injury through a mitigation of Ca 2+ overload induced by downregulation of the CaR [ 222 ].…”

Xuan Bi Tong Yu Fang Promotes Angiogenesis via VEGF‐Notch1/Dll4 Pathway in Myocardial Ischemic Rats

“…When the structure and function of mitochondria become abnormal, cardiomyocyte apoptosis will be induced [28]. Dysfunction of energy metabolism in myocardial cells is an important pathological basis of myocardial ischemia [27], and maintaining the functional stability of mitochondria in myocardial cells and the metabolic balance of ATP can effectively alleviate myocardial injury [29,30]. He and He [31] found that resveratrol reduced mitochondrial damage in myocardial cells, inhibited inflammatory reaction, and reduced myocardial cell apoptosis.…”

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

“…Under physiological conditions, Ca 2+ enters cardiomyocytes through the L-type Ca 2+ channel (LTCC) and the β-adrenergic receptor (β-AR), causing the release of a large amount of Ca 2+ from the Sarcoplasmic Reticulum (SR) through activation of the RyR and leading to contraction. However, under some pathological conditions, such as pulmonary hypertension, myocardial ischemia, and cardiac hypertrophy, CaSR expression is upregulated, leading to [Ca 2+ ] i enhancement and thus aggravating the progression of these diseases ( Guo et al, 2012 , 2017 ; Zhang et al, 2016 ). Upon review of the previous studies, it was found that CaSR contributes to cardiac hypertrophy induced by angiotensin II, Iso, and transverse aortic constriction, and the mechanism may involve [Ca 2+ ] i , the sarcoplasmic reticulum (ER), the mitochondrial death pathway and autophagy ( Wang et al, 2008 ; Lu et al, 2013 ; Liu L. et al, 2016 ).…”