Cardiac preconditioning with calcium: Clinically accessible myocardial protection

Abstract

Cardiac preconditioning is mediated by protein kinase C. Although endogenous calcium is a potent stimulus of protein kinase C, it remains unknown whether preischemic administration of exogenous calcium can induce protein kinase C-mediated myocardial protection against ischemia-reperfusion injury. To study this, calcium chloride was administered retrogradely through the aorta at a rate 5 nmol/min for 2 minutes to isolated perfused rat hearts 10 minutes before a 20-minute ischemia and 40-minute reperfusion insult. Calcium-mediated cardioadaptation was then linked to protein kinase C by means of the protein kinase C inhibitor chelerythrine (20 mumol.L-1.2 min-1). To determine whether exogenous calcium administration induces protein kinase C translocation and activation, immunohistochemical staining for the calcium-dependent protein kinase C isoform alpha was performed on adjacent 5 microns myocardial sections with and without calcium chloride treatment. Results indicated that preischemic calcium chloride administration improved myocardial functional recovery, as determined by enhanced developed pressure, improved coronary flow, reduced end-diastolic pressure, and decreased creatine kinase leakage during reperfusion. Beneficial effects of calcium chloride were eliminated by concurrent protein kinase C inhibition. Immunohistochemical staining for the alpha isoform of protein kinase C demonstrated that calcium chloride induces translocation of this isoform from the cytoplasm to the sarcolemma, indicating that exogenous calcium administration activates this isoform. These results suggest that calcium chloride, a safe and routinely administered agent, can induce protein kinase C-mediated cardiac preconditioning. Calcium-induced cardioadaptation to ischemia-reperfusion injury may be promising as a clinically feasible therapy before planned ischemic events such as cardiac allograft preservation and elective cardiac operations.

Adaptive and Maladaptive Mechanisms of Cellular Priming

“…'-" All surgical disci- 12,[28][29][30][31][32][33][34][35][36]38,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] (Fig. 1).…”

Protein kinase Cϵ interacts with cytochrome c oxidase subunit IV and enhances cytochrome c oxidase activity in neonatal cardiac myocyte preconditioning

“…Reactions were terminated by the addition of SDS Laemmli sample buffer at 90 • C. Samples were then heated for 5 min and subjected to SDS/PAGE. [8][9][10][11][12][13][14][15][16][17]] These peptides were then conjugated to the protein transducing domain of the HIV-Tat protein (amino acids 47-57) as described previously [37]. An HIV-Tat carrier-carrier peptide (YGRKKRRQRRR-YGRKKRRQRRR) was synthesized as a control.…”

“…Experimentally, it is the most powerful form of cardiac protection known and it has been demonstrated in cardiac myocytes [2][3][4][5], intact hearts [6,7] and many animal species [8][9][10][11], including humans [12][13][14]. Downstream signalling molecules reported to be involved in PC include ATPdependent potassium channels [4,12,15,16], PKC (protein kinase C) isoenzymes [2, 3,12,15,17,18], MAPK (mitogen-activated protein kinase) enzymes [19][20][21], tyrosine kinases [22][23][24], PI3K (phosphoinositide 3-kinase) [22,25], heat-shock proteins [5,16,26], nitric oxide [27][28][29], free radicals [21,25,30] etc.…”

Calcium Preconditioning, but Not Ischemic Preconditioning, Bypasses the Adenosine Triphosphate-Dependent Potassium (KATP) Channel

“…The stress hormones adenosine, bradykinin, and norepinephrine induce the early phase of preconditioning through the activation of intracellular kinases such as protein kinase C. Subsequent phosphorylation of signaling enzymes (acute preconditioning) and/or synthesis of stress proteins (delayed preconditioning) are the endogenous mechanisms which protect myocardium against a subsequent ischemic insult by decreasing necrosis and apoptosis, improving contractility, and promoting resistance to reperfusion arrhythmias [1][2][3][4][5][6][7][8][9][10][11][13][14][15][16]. Similarly, the induction of calcium stress by transiently increasing the extracellular calcium concentration also induces preconditioning-like protection (calcium preconditioning) [17,18]. Extracellular signals trigger cell-surface receptors which activate intracellular second messengers and effectors.…”

“…Ischemic preconditioning was induced by inducing 2 min of global myocardial ischemia followed by 10 min of reperfusion and standard I/R. Calcium preconditioning was induced by infusing 1 mM CaCl 2 for 2 min followed by 10 min of perfusion (washout) and standard I/R [17,18,22,23]. To determine whether the observed protective effects of calcium preconditioning or ischemic preconditioning were mediated by K ATP channel, the K ATP channel inhibitor glibenclamide (10 mol/ liter) was administered prior to ischemic preconditioning or calcium preconditioning.…”