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KMUP‐3 attenuates ventricular remodelling after myocardial infarction through eNOS enhancement and restoration of MMP‐9/TIMP‐1 balance
Author(s) -
Liu ChungPin,
Yeh JwuLai,
Wu BinNan,
Chai CheeYin,
Chen IngJun,
Lai WenTer
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01024.x
Subject(s) - enos , myocardial infarction , matrix metalloproteinase , nitric oxide , medicine , cardiology , nitric oxide synthase , pharmacology
BACKGROUND AND PURPOSE Previously, 7‐[2‐[4‐(4‐nitrobenzene)piperazinyl]ethyl]‐1, 3‐dimethylxanthine (KMUP‐3) has been shown to induce aortic smooth muscle relaxation through K ATP 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 APPROACH Wistar 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 −1 ·day −1 ) 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‐β‐stimulated human cardiac fibroblasts. KEY RESULTS KMUP‐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 ω ‐nitro‐L‐arginine methyl ester. CONCLUSIONS AND IMPLICATIONS The K ATP 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.