Cardioprotective Effect Of Postconditioning Research Articles

Involvement of Protein Kinase C-δ in the Realization of Cardioprotective Effect of Ischemic Postconditioning.

Experiments on isolated perfused rat heart modeled 45-min global ischemia followed by 30-min reperfusion. Ischemic postconditioning was modeled by 3 cycles of reperfusion (30 sec) and ischemia (30 sec). Cardiomyocyte necrosis was assessed by the level of creatine phosphokinase in the perfusate. Postconditioning reduced the release of creatine phosphokinase from the heart by 30%. The cardioprotective effect of ischemic postconditioning was eliminated after inhibition of protein kinase C with cheleritrin or after blockade of δ-isoform of protein kinase C with rottlerin. These findings attest to participation of protein kinase C-δ in the realization of the cardioprotective effect of postconditioning.

Postconditioning the Heart: Analysis of Experimental and Clinical Data

Experimental atherosclerosis and hypercholesterolemia may reduce or eliminate the infarct-limiting and anti-apoptotic effect of postconditioning (PC). Experiments in rats and mice indicate that the PC may be quite effective in patients with diabetes type 2 or metabolic syndrome. Experimental data suggest that hypertension or the past myocardial infarction is not an obstacle for the implementation of cardioprotective effect of PC. It was established that that aging does not preclude the implementation of PC cardioprotective effect. Inotropic effect of IP can simulate on isolated human atrial trabeculae. The clinical observations suggest that the PC in patients with tetralogy of Fallot and patients with operations on the valves improves the outcome of cardiac surgery. It was established that PC in these patients reduces the intensity of reperfusion necrosis of cardiomyocytes, improves the pumping function of the heart, reduces the inotropic support, shorten the extubation time.

Hypoxic Postconditioning Inhibits Endoplasmic Reticulum Stress–Mediated Cardiomyocyte Apoptosis by Targeting PUMA

Postconditioning prevents cardiomyocytes from ischemia/reperfusion-induced apoptosis. However, little is known about the molecular mechanisms that mediate the cardioprotective effect of postconditioning. Here, we hypothesized that postconditioning targeted p53 upregulated modulator of apoptosis (PUMA) to protect cardiomyocytes against endoplasmic reticulum stress-mediated apoptosis. Our results demonstrated that postconditioning could inhibit GRP78 (78-kDa glucose-regulated protein) expression, caspase-12 activation, and cardiomyocyte apoptosis by regulating PUMA expression. In addition, p53 is involved in the regulatory role of postconditioning in PUMA expression. Our data reveal a cardioprotective pathway of postconditioning in which it represses PUMA.

Activation of cGMP/Protein Kinase G Pathway in Postconditioned Myocardium Depends on Reduced Oxidative Stress and Preserved Endothelial Nitric Oxide Synthase Coupling

BackgroundThe cGMP/protein kinase G (PKG) pathway is involved in the cardioprotective effects of postconditioning (PoCo). Although PKG signaling in PoCo has been proposed to depend on the activation of the phosphatidylinositol 3‐kinase (PI3K)/Akt cascade, recent data bring into question a causal role of reperfusion injury signaling kinase (RISK) in PoCo protection. We hypothesized that PoCo increases PKG activity by reducing oxidative stress–induced endothelial nitric oxide synthase (NOS) uncoupling at the onset of reperfusion.Methods and ResultsIsolated rat hearts were submitted to 40 minutes of ischemia and reperfusion with and without a PoCo protocol. PoCo reduced infarct size by 48% and cGMP depletion. Blockade of cGMP synthesis (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one) and inhibition of PKG (KT5823) or NOS (l‐NAME) abolished protection, but inhibition of PI3K/Akt cascade (LY294002) did not (n=5 to 7 per group). Phosphorylation of the RISK pathway was higher in PoCo hearts. However, this difference is due to increased cell death in control hearts because in hearts reperfused with the contractile inhibitor blebbistatin, a drug effective in preventing cell death at the onset of reperfusion, RISK phosphorylation increased during reperfusion without differences between control and PoCo groups. In these hearts, PoCo reduced the production of superoxide (O2−) and protein nitrotyrosylation and increased nitrate/nitrite levels in parallel with a significant decrease in the oxidation of tetrahydrobiopterin (BH4) and in the monomeric form of endothelial NOS.ConclusionsThese results demonstrate that PoCo activates the cGMP/PKG pathway via a mechanism independent of the PI3K/Akt cascade and dependent on the reduction of O2− production at the onset of reperfusion, resulting in attenuated oxidation of BH4 and reduced NOS uncoupling.

Abstract 374: Targeted Deletion of A 2B Adenosine Receptors Attenuates the Protective Effects of Myocardial Postconditioning

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (PostCon). To assess the hypothesis that A 2B adenosine receptor (A 2B AR) activation contributes to PostCon-induced protection, global ischemia-reperfusion was performed with and without PostCon or the selective A 2B agonist, BAY 60 – 6583 (BAY), in isolated wild-type (WT) and A 2B AR knockout (A 2B KO) mouse hearts. In WT hearts, PostCon improved post-ischemic recovery of left ventricular developed pressure (LVDP) to 63.3±1.6 % of pre-ischemic baseline vs. 49.9±1.6 % in non-PostCon controls (CTL), lowered end diastolic pressure (EDP) to 15.8±1.5 mmHg vs. 27.9±1.6 mmHg in CTL, and reduced coronary efflux of cardiac troponin I (cTnI) to 2507±359 ng/g heart weight vs. 4693±343 ng/g in CTL (n=12 both groups, p <0.05 each comparison). Treatment with BAY in the first two min of reperfusion mimicked beneficial effects of PostCon in WT hearts (LVDP: 64.7±2.0 % baseline, EDP: 16.2±2.0 mmHg, cTnI: 3311±366; n=13, not significant compared to respective PostCon values). Real-time PCR confirmed absence of A 2B AR in A 2B KO hearts and demonstrated no changes in expression of other adenosine receptor subtypes compared with WT hearts. In A 2B KO hearts, neither PostCon nor BAY improved recovery of LVDP (50.8±1.6 % baseline for CTL vs. 54.5±1.7 % with PostCon vs. 53.0±1.4 with BAY; n=6 each group), and neither affected EDP or release of cTnI. During reperfusion, both PostCon and BAY increased survival kinase signaling through Akt and ERK1/2 phosphorylation in WT but not A 2B KO hearts. In non-ischemic WT hearts, Akt and ERK1/2 phosphorylation was increased by both BAY treatment and application of the PostCon stimulus. These data demonstrate that the protective effects of PostCon are attenuated by targeted deletion of A 2B AR and are mimicked by selective A 2B AR activation, suggesting A 2B AR activation is an important trigger leading to PostCon-induced myocardial protection.