title: Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction.
abstract: In this study, we used the somatic gene delivery approach to explore the role of the kallikrein-kinin system (KKS) in cardiac remodeling and apoptosis after myocardial infarction (MI). Rats were subjected to coronary artery ligation to induce MI, and adenovirus carrying the human tissue kallikrein or luciferase gene was injected into the tail vein at 1 week after surgery. Cardiac output gradually decreased from 2 to 6 weeks after MI, whereas delivery of the kallikrein gene prevented this decrease. Cardiac responses to dobutamine-induced stress were improved in rats receiving kallikrein gene as compared with rats receiving control virus at 6 weeks after MI. Kallikrein significantly improved cardiac remodeling by decreasing collagen density, cardiomyocyte size, and left ventricular internal perimeter and increasing capillary density in the heart at 6 weeks after MI. Kallikrein gene transfer attenuated myocardial apoptosis, which was positively correlated with remodeling parameters in the heart at 2 weeks after MI. Endothelial dysfunction, characterized by increased vascular resistance, decreased left ventricular blood flow, and decreased cardiac nitric oxide levels, existed in remodeled hearts at 2 weeks after MI, whereas kallikrein gene transfer improved these parameters. Kallikrein gene delivery improved cell survival parameters as shown by increased phospho-Akt and reduced caspase-3 activation at 2 weeks after MI. This study indicates that the kallikrein-kinin system plays an important role in preventing the progression of heart failure by attenuating cardiac hypertrophy and fibrosis, improving endothelial function, and inhibiting myocardial apoptosis through the Akt-mediated signaling pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Agata
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D004195:Disease Models, Animal; D004280:Dobutamine; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology; D007610:Kallikreins / Q000008:administration & dosage* / Q000235:genetics; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D009566:Nitrates; D009573:Nitrites; D011518:Proto-Oncogene Proteins; D004280:Dobutamine; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D007610:Kallikreins