Losartan preserves integrity of cardiac gap junctions and PGC-1 alpha gene expression and prevents cellular apoptosis in remote area of left ventricular myocardium following acute myocardial infarction.
This study tests the hypothesis that peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha) and the integrity of gap junctions (GJs) were suppressed and the number of apoptotic bodies was increased in remote viable areas of left ventricle following acute myocardial infarction (AMI), which can be reversed by losartan therapy. Open chest surgery was consecutively performed on 32 adult male Sprague-Dawley rats. These rats were classified into 4 groups (n = 8/each group): group I, AMI (by ligation of left coronary artery (LCA) without treatment); group II, AMI with losartan 20 mg/kg/day; group III, sham control (without LAD ligation); and group IV, sham control with losartan 20 mg/kg/day. Echocardiography was performed on day 1 prior to AMI and on day 14 just before the rats were to be sacrificed for cellular and molecular studies. The results showed that mRNA expression of PGC-1alpha, integrated area (microm(2)) of clustered connexin43 (Cx43) spots, and Cx43 GJs were substantially down-regulated and the number of apoptotic bodies was markedly increased in nontreated AMI rats compared with healthy control and losartan-treated AMI rats on day 14 following AMI (all values of P < 0.001). Additionally, day 14 left ventricular (LV) ejection fraction was significantly lower in nontreated AMI rats than in healthy control and losartan-treated AMI rats (all values of P < 0.0001). Down-regulation of GJs and PGC-1alpha gene expression and cellular death were frequently observed in remote viable areas of LV following AMI. Losartan therapy reversed the adverse effects of AMI and preserved LV function.
Sun
Cheuk-Kwan
CK
Department of General Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Chang
Li-Teh
LT
Sheu
Jiunn-Jye
JJ
Wang
Chi-Young
CY
Youssef
Ali A
AA
Wu
Chiung-Jen
CJ
Chua
Sarah
S
Yip
Hon-Kan
HK
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015536:Down-Regulation; D017629:Gap Junctions / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology; D006360:Heat-Shock Proteins / Q000235:genetics*; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics*