Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors

Abstract

Background: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Methods: Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. Results: MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. Conclusions: This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis

“…Encouraging results have been reported for doxycycline (MMP inhibitor) in reducing adverse LV remodeling in ST-segment elevation myocardial infarction (STEMI) patients (Tetracycline (Doxycycline) and Post Myocardial Infarction Remodeling TIPTOP trial) [105] and for metformin (AMPK activator) in reducing left ventricular mass indexed to height in non-diabetic patients with coronary artery disease (MET-REMODEL trial) [108]. These results add to overwhelming evidence implicating MMPs and AMPK in the pathogenesis of adverse cardiac remodeling in hypertension, myocardial infarction, and heart failure [59,61,[110][111][112][113][114][115][116][117][118][119][120] (all of which are comorbidities in COVID-19).…”

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

“…MMP-2 also cleaves and activates GSK-3 in the cytosol, which may contribute to cardiac damage [ 125 ]. Consequently, inhibiting intracellular MMP-2 activities in hearts during ischemia/reperfusion was found to exert cardioprotective effects [ 126 , 127 ]. It is worth mentioning that TIMP-4 was also found within thin myofilaments inside cardiomyocytes, which indicates a potential regulatory role of TIMPs inside cells [ 128 ].…”

The Synergistic Effects of Astragalus mongholicus and Salvia miltiorrhiza on Coronary Heart Disease Identified by Network Pharmacology and Experiment

“…Myocardial infarct size was quantitatively detected by TTC staining. 25 The hearts were rapidly frozen (−20 °C for 1 h), cut into 4-mm thick slices (total of three), and each slice was incubated at 37°C in 1 mL of 1% TTC (dissolved in pH 7.4 phosphate buffer) for 10 min. The TTC entered the normal cells and bound to dehydrogenase in red, while dead cells were not stained by TTC due to the lack of dehydrogenase.…”