Post-myocardial infarct p27 fusion protein intravenous delivery averts adverse remodelling and improves heart function and survival in rodents

• Published in: Cardiovascular research Vol. 94; no. 3; pp. 492 - 500
• Main Authors: KONECNY, Filip, JIAN ZOU, HUSAIN, Mansoor, HARSDORF, Rüdiger Von
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.2012
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Cardiology. Vascular system; Coronary heart disease; Cyclin-Dependent Kinase Inhibitor p27 - administration & dosage; Cyclin-Dependent Kinase Inhibitor p27 - therapeutic use; Fibrosis - drug therapy; Heart; Heart - drug effects; Heart - physiopathology; Injections, Intravenous; Male; Medical sciences; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocarditis. Cardiomyopathies; Rats; Rats, Inbred F344; Ventricular Remodeling - drug effects; Heart; Myocardial infarction; Prognosis; Intravenous administration; Cell cycle inhibitor; Rodentia; Cardiovascular disease; Coronary heart disease; Myocardial disease; Phlebology; Survival; Vertebrata; Mammalia; Animal; Cell cycle; Inhibitor; Circulatory system; Myocardial infarct; Cardiology; Fusion protein; TAT fusion protein p27; Apoptosis; Hyperthrophy
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvs138

P27Kip1 (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase 2 (cdk-2). Despite robust expression in the heart, little is known about the regulation and function of p27 in this terminally differentiated tissue. Previously, we demonstrated that p27 exerts anti-apoptotic and growth-inhibitory effects through interaction with casein kinase 2 (ck2) in neonatal rat cardiomyocytes. Here, we test the hypothesis that delivery of a transactivator of transcription (TAT)-p27 fusion protein (TAT.p27) will improve cardiac function and survival in a rat model of myocardial infarction (MI). Fisher rats underwent permanent left anterior descending ligation-induced MI followed by iv injection of TAT.p27 or TAT.LacZ (20 mg/kg) on Days 1 and 7 post-MI. Delivery of TAT.p27 was evaluated by western blot (WB) and immunofluorescence microscopy. Heart function was assessed by echocardiography and pressure-volume catheter. Apoptosis, hypertrophy, and fibrosis were detected by histochemistry and morphometry. WB confirmed gradual reduction in endogenous cardiac p27 levels following MI, with immunohistochemistry demonstrating successful delivery of TAT.p27 to the heart. At 48 h post-MI, cardiac apoptosis was decreased in rats treated with TAT.p27 when compared with saline- and TAT.LacZ-treated controls. At 28 days post-MI, rats treated with TAT.p27 manifested less cardiomyocyte hypertrophy and fibrosis, less diminished cardiac function, and greater survival. Additionally, p27KO mice undergoing experimental MI suffered an early increase in apoptosis with a larger infarct size and markedly reduced survival when compared with wild-type (WT) controls. These gain- and loss-of-function studies reveal a critical role for p27 in cardiac remodelling post-MI.