Exercise Increases Myocardial TIMP‐2 Protein Levels and Is Associated with Cardioprotection against Myocardial Ischemia‐Reperfusion Injury

Abstract

Coronary artery disease (CAD) remains the leading cause of death worldwide. The most common manifestation of CAD is myocardial infarction (MI), a result of ischemia and/or reperfusion (IR) injury of the myocardium. It is well established that exercise training improves myocardial tolerance to IR, a phenomenon known as exercise‐induced cardioprotection, but the cellular adaptations resulting in cardioprotection against IR injury are not well understood. Recent work has linked IR injury to the activation of the matrix metalloproteinase‐2 (MMP‐2). MMPs are known to be involved in the degradation of the extracellular matrix, and play a key role in scar formation following MI. While this extracellular role of MMP‐2 in MI has been well established, recent studies suggest an additional, intracellular, role of MMP activation in IR injury. MMP‐2 has been shown to have intracellular proteolytic targets in cardiomyocytes, which could contribute to the cell death seen following IR. Tissue inhibitor of metalloproteinases (TIMPs) are inhibitors of the MMPs, and TIMPs have been found in cardiomyocytes. It is thus possible that exercise provides cardioprotection against IR injury through 1) decreasing MMP‐2 protein levels, or 2) inhibiting MMP‐activation by increasing the protein levels of the TIMPs. However, no study to date has investigated the effect of exercise training on the protein levels of MMP‐2 and TIMP‐2 following IR injury. Therefore, the specific aims of this study were to determine the effects of exercise training on MMP‐2 and TIMP‐2 protein expression, and to identify regional differences in the levels of these proteins. To address these questions, we studied 3‐month old Sprague‐Dawley rats randomly assigned to sedentary (SED) or exercise (EX) groups (n=10/group). EX rats were run on a treadmill for 60 min/day, 5 days/week, for 8 weeks. IR was induced by occluding the LAD for 45 min, followed by 24 hr of reperfusion. Hearts were excised and sectioned and stained to delineate the zone at risk (ZAR) from the unaffected area (UA). Infarct size was expressed as a percentage of the ZAR. Hearts from EX rats exhibited smaller infarcts compared to SED rats (21.4% vs. 37.2%; P < 0.05). MMP‐2 and TIMP‐2 levels in ventricular homogenates were determined by Western blot. MMP‐2 protein content was increased in the ZAR compared to the UA in both EX and SED rats (P < 0.05). There was no difference in MMP‐2 protein levels between EX or SED rats. TIMP‐2 protein levels were increased in the hearts from EX rats compared to SED rats (P < 0.05). There was no difference in TIMP‐2 levels between the ZAR and UA in EX or SED rats. These results show that 1) MMP‐2 levels were significantly higher in the ZAR compared to the UA, suggesting an intracellular role of MMP‐2 in IR injury, and 2) exercise training leads to an increase in myocardial TIMP‐2 protein levels, suggesting elevated TIMP‐2 inhibition of MMP‐2 as a potential mechanism of exercise‐induced cardioprotection.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.