QUINAPRIL AMELIORATES CARDIAC REMODELING IN DIABETIC RATS VIA SUPPRESSION OF EGR1 AND STAT3 ACTIVATION

Abstract

Objective: RAAS over activation in diabetes may induce myocardial hypertrophy and extracellular matrix accumulation even without hypertension, and ACE-inhibitors are widely used to manage blood pressure. STAT3 activation is known to promote experimental kidney remodeling, but its role in diabetic myocardium has not been elucidated. Experimental evidence shows that EGR1 contributes to myocardial remodeling, yet the effect of ACE-inhibition on myocardial EGR1 in diabetes is still unknown. Thus, we investigated whether the ACE-inhibitor quinapril could influence myocardial EGR1 and STAT3 activation in diabetic rats. Design and method: Male Sprague-Dawley rats (250–300 g, n=12) were ip. injected with 60 mg/kg streptozotocin to induce type-1 diabetes (DM). Half of DM rats was treated with 50 mg/kg/day quinapril in drinking water (Q) for 8 weeks. Non-diabetic littermates served as negative controls (CTL). Experimental groups were as follows (n = 6/group): 1) CTL; 2) DM; 3) DM+Q. At harvest, plasma renin activity (PRA) was assessed and myocardium was processed for histology, immunohistochemistry, mRNA and protein expression analyses. Data are presented as mean ± SD, analyzed using Kruskal-Wallis test with Dunn's post-hoc test. Results: PRA was elevated in diabetic groups regardless of treatment (CTL:1.3 ± 0.2, DM:2.2 ± 1.0, DM+Q:1.8 ± 1.1 ng/ml/h, p < 0.05), accompanied by myocardial (pro)renin receptor (PRR) mRNA overexpression (fold expression, CTL:1.0 ± 0,2, DM:1.8 ± 0.9, DM+Q:1.7 ± 0.5, p < 0.05). However, quinapril reduced collagen-1 mRNA expression (CTL:1.0 ± 0.3, DM:1.3 ± 0.4, DM+Q:0.7 ± 0.3, p < 0.01) and fibronectin immunoreactivity, accompanied by reduced matrix remodeling shown by the expression of both tissue inhibitor of metalloproteases TIMP1 and TIMP2 (TIMP1, CTL:0.9 ± 0.1, DM:1.6 ± 0.7, DM+Q:1.0 ± 0.5, p < 0.05; TIMP2, CTL:1.0 ± 0.1, DM:1.8 ± 0.5, DM+Q:1.1 ± 0.4, p < 0.05). Immunoblots showed that quinapril also attenuated diabetes induced EGR1 protein expression (CTL:1.0 ± 0.4, DM:1.8 ± 0.5, DM+Q:0.5 ± 0.2, p < 0.01) and STAT3 phosphorylation (CTL:1.0 ± 0.1, DM:1.4 ± 0.2, DM+Q:0.6 ± 0.1, p < 0.01), accompanied by reduced TIMP1 protein expression (CTL:0.9 ± 0.1, DM:1.5 ± 0.3, DM+Q:0.9 ± 0.3, p < 0.05) that correlated with STAT3 activity (R-square: 0.4, p = 0.03). Conclusions: In our rat model of type-1 diabetes, chronic quinapril treatment significantly attenuated cardiac remodeling via its direct inhibitory effect on the profibrotic myocardial EGR1 and STAT3. These results underscore the tissue-specific, blood pressure-independent beneficial effects of ACE inhibition in diabetes.