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


METHODS
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.


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
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.
Liu
Chung-Pin
CP
Depart of Internal Medicine, Yuan's General hospital, Kaohsiung, Taiwan.
Yeh
Jwu-Lai
JL
Wu
Bin-Nan
BN
Chai
Chee-Yin
CY
Chen
Ing-Jun
IJ
Lai
Wen-Ter
WT
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D006439:Hemodynamics; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*
C508169:7-(2-(4-(4-nitrobenzene)piperazinyl)ethyl)-1,3-dimethylxanthine; D010880:Piperidines; D019715:Tissue Inhibitor of Metalloproteinase-1; D014970:Xanthines; D052250:Nitric Oxide Synthase Type III; D020780:Matrix Metalloproteinase 9