Increased expression of calcium‐sensing receptors induced by ox‐LDL amplifies apoptosis of cardiomyocytes during simulated ischaemia–reperfusion

Abstract

1. Acute myocardial infarction (AMI) is strongly associated with atherosclerosis, and is responsible for significant morbidity and mortality worldwide. The pathogenic mechanisms that underlie atherosclerosis and AMI are undefined at present. The calcium-sensing receptor (CaSR) is a member of the superfamily of G-protein coupled receptors. It has been demonstrated previously that the expression of CaSR is increased in atherosclerotic cardiac tissue of rats. It has also been suggested that CaSR has a crucial role in cardiac ischaemia-reperfusion injury, apoptosis and hypertrophy. However, it remains to be determined whether an increase in the expression of CaSR influences the sensitivity of cardiomyocytes to AMI. 2. The present study used cultured ventricular cardiomyocytes from neonatal rats to investigate the effect of oxidized low-density lipoprotein (ox-LDL), ischaemia-reperfusion, GdCl(3) (an agonist of CaSR) and NPS-2390 (an antagonist of CaSR) on the expression of CaSR. The amount of apoptosis, alterations in the morphology of the cells, the intracellular calcium concentration ([Ca(2+)](i)) and components of critical mitochondrial pathways were also analysed. 3. Cardiomyocytes treated with ox-LDL showed upregulated expression of CaSR, cytochrome c (cyt-c), Bax and activated caspase 3 (17 kD) and downregulated expression of Bcl-2, as well as elevated [Ca(2+)](i) and apoptosis. Application of GdCl(3) augmented these effects, and NPS-2390 decreased the expression of CaSR and reduced apoptosis. 4. In conclusion, ox-LDL was found to increase the expression of CaSR in a manner that was dependent on time and dose. It also augmented apoptosis during simulated ischaemia-reperfusion in cultured ventricular cardiomyocytes from neonatal rats.

Oxidized low-density lipoprotein (oxLDL) affects load-free cell shortening of cardiomyocytes in a proprotein convertase subtilisin/kexin 9 (PCSK9)-dependent way

“…On the level of cardiomyocytes, oxLDL had been associated with induction of apoptosis, alterations in generation of action potential, and induction of gene transcription that is normally linked to cardiac remodeling (BNP, MCP-1). Unfortunately, such experiments were always performed with cells that cannot be directly compared to terminally differentiated ventricular cardiomyocytes [ 2 , 8 ]. Experiments that were performed on rabbit cardiomyocytes are an exception [ 36 ].…”

“…Of note, plasma levels of oxLDL have been associated with a decrease in cardiac function independent of vascular alterations [ 21 ]. Furthermore, oxLDL induced apoptosis in neonatal rat cardiomyocytes [ 8 ], it prolonged action potential and it depolarized resting potential in rabbit cardiomyocytes [ 36 ]. OxLDL induced the expression of biomarkers associated with heart failure in HL-1 cells, an immortalized cardiac-like cell type [ 2 ].…”

Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression

“…Recent studies show that ischemia also increases CaSR expression in cardiomyocytes and leads to apoptosis [29, 30]. Further investigations indicate that the CaSR activation is important for the cardioprotection induced by ischemic preconditioning of cardiomyocytes [31].…”

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

“…Activation of LOX-1 receptors subsequently induced cellular apoptosis [182]. oxLDL increases further the expression of calcium-sensing receptors (CaSR) that link extracellular calcium to intracellular calcium transients and contractility in cardiomyocytes [70, 168]. Whether the induction of apoptosis induced by doxorubicin requires an up-regulation and/or activation of CaSR is not known.…”