Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation.

We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9-deficient and wild-type mice. The number of α-smooth muscle actin (αSMA)-positive myofibroblasts and αSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9-deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-κB and the number of αSMA-positive and αSMA/Ki67-double-positive cells and these increases were attenuated by BAY1-7082, an NF-κB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-κB activation or the number of αSMA-positive and αSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts.

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

Repeated physiologic stresses provide persistent cardioprotection against ischemia-reperfusion injury in rats.

OBJECTIVES: We investigated the time course of myocardial tolerance to ischemia-reperfusion injury after repeated physiologic or pharmacologic stresses. BACKGROUND: Sublethal stress provides cardiac tolerance to ischemia-reperfusion injury and increases the activity of manganese superoxide dismutase (Mn-SOD) in the myocardium in a biphasic manner. However, few studies have investigated the time course of the cardioprotective effects after repeated stresses. METHODS: One or two episodes of the same physiologic or pharmacologic stress (exercise, whole-body hyperthermia, or tumor necrosis factor-alpha treatment), or a combination of two different types of stress, were induced after a 48-h interval. The rats were then subjected to 20 min of left coronary artery occlusion, followed by 48 h of reperfusion. The interval between the last stimulus and the induced ischemia was between 0.5 h and 168 h. The incidence of ventricular fibrillation during ischemia and the size of the myocardial infarct after reperfusion were then examined. RESULTS: When two episodes of physiologic or pharmacologic stress were induced, the beneficial effects against ischemia-reperfusion injury were observed in a monophasic manner. These effects persisted for a period of 0.5 to 60 h. One episode of sublethal stress provoked the same beneficial effects, but in a biphasic manner. The increase in Mn-SOD activity in the cardiac tissue resembled the time course for cardioprotection against ischemia-reperfusion injury. CONCLUSIONS: Two episodes of physiologic or pharmacologic stress can provide persistent cardioprotective effects against ischemia-reperfusion injury.