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.
Highlights
Strategies to limit myocardial ischemia-reperfusion (I/R) injury have not been well applied in clinical settings
There were apparent increases (P < 0.05) in glibenclamide + Ischemic postconditioning (IPC) and spermine + IPC groups compared with A/R group. It indicated that pinacidil (30 or 100 mM) strongly inhibited [Ca2+]i, while the calcium-sensing receptor (CaSR) agonist spermine remarkably increased the [Ca2+]i levels in adult rat cardiomyocytes after I/R injury
Myocardial I/R injury is one of the leading causes of morbidity. [Ca2+]i overload during I/R injury is the trigger of cell damage
Summary
Strategies to limit myocardial ischemia-reperfusion (I/R) injury have not been well applied in clinical settings. Following the finding of the mitochondrial KATP that locating at the inner membrane of mitochondria in 1991 (Inoue et al, 1991), Garlid et al (1997) and Liu et al (1998) demonstrated it as a trigger of ischemic preconditioning. It’s demonstrated that pharmacologically inhibition of KATP in early reperfusion abolished the infarct-limiting effects of IPC (Donato et al, 2007; Mykytenko et al, 2008; Yang et al, 2004). The possible mechanisms of KATP in I/R hearts were various: swelling of mitochondria, increased fatty acid oxidation, ATP production and mitochondrial respiration in heart (Halestrap, 1989); inhibition of ATP hydrolysis during ischemia (Belisle & Kowaltowski, 2002; Dzeja et al, 2003); preservation of ATP and reduction of Ca2+ overload in caydiomyocytes (Cao et al, 2015)
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