KMUP‐3 attenuates ventricular remodelling after myocardial infarction through eNOS enhancement and restoration of MMP‐9/TIMP‐1 balance

Abstract

BACKGROUND AND PURPOSE Previously,piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) has been shown to induce aortic smooth muscle relaxation through KATP channel opening and endothelial nitric oxide synthase (eNOS) enhancement. We further investigated whether KMUP-3 protects against myocardial remodelling after myocardial infarction (MI), and whether KMUP-3 increases the expression of eNOS in MI rats. EXPERIMENTAL APPROACHWistar rats were randomly allocated into three groups: MI (n = 10), MI + KMUP-3 group (n = 10) and sham group (n = 10). MI was induced by ligation of the left anterior descending coronary artery. After recovery, the MI + KMUP-3 group received KMUP-3 (0.3 mg·kg) infusion for 4 weeks, while the MI and sham group received vehicle only. To further confirm that the effect of KMUP-3 is dependent on eNOS, KMUP-3 was applied in the culture of transforming growth factor-b-stimulated human cardiac fibroblasts. KEY RESULTSKMUP-3 treatment attenuated cardiac hypertrophy post-MI and improved cardiac function. The fibrotic area was reduced by KMUP-3 both in central-, peri-and non-infarction areas. KMUP-3 enhanced the expression of eNOS and tissue inhibitor of metalloproteinase-1 (TIMP-1), but reduced matrix metalloproteinase-9 (MMP-9) expression. In vitro, the activities of KMUP-3 were blocked by pretreatment with the eNOS inhibitor N w -nitro-L-arginine methyl ester. CONCLUSIONS AND IMPLICATIONSThe KATP channel opener KMUP-3 preserved cardiac function after MI by enhancing the expression of eNOS. In addition, KMUP-3 restored the myocardial MMP-9/TIMP-1 balance and attenuated ventricular remodelling by an eNOS-dependent mechanism. AbbreviationsAMI, acute myocardial infarction; + dP/dt and -dP/dt, maximum rate of rise and full of pressure; eNOS, endothelial nitric oxide synthase; FS, fractional shortening; HCF, Human cardiac fibroblast; HUVEC, human umbilical vein endothelial cell; KATP channel, ATP-dependent potassium channel; LAD, left anterior descending coronary artery; L-NAME, N w -nitro-L-arginine methyl ester; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; LVSP, left ventricular systolic pressure; MI, myocardial infarction; MMP-9, matrix metalloproteinase-9; NO, nitric oxide; PKG, protein kinase G; TGF-b, transforming growth factor-b; TIMP-1, tissue inhibitor of metalloproteinase-1 BJP British Journal of Pharmacology

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