title: Overexpression of cdk Inhibitor p16INK4a by adenovirus vector inhibits cardiac hypertrophy in vitro and in vivo: a novel strategy for the gene therapy of cardiac hypertrophy.
abstract: Cardiac hypertrophy is one of the serious complications which increase mortality due to cardiovascular diseases. However, only a partial reduction of cardiac hypertrophy has been successful using current drug therapy. We demonstrate here reduction of cardiac hypertrophy in vitro and in vivo using an adenovirus vector encoding cyclin-dependent kinase (cdk) inhibitor p16INK4a. Adenovirus-mediated overexpression of cdk inhibitor p16INK4a completely inhibited cardiac myocyte hypertrophy induced by endothelin (ET)-1, as evaluated by [3H]leucine incorporation into the cells and mRNA levels of skeletal alpha -actin (SK-A) or atrial natriuretic peptide (ANP) as well as by morphometric analyses. We then evaluated whether p16INK4a can suppress left-ventricular (LV) hypertrophy induced by aortic banding (AOB) in rats. Catheter-mediated gene transfer of AxCAp16 was performed according to the method reported by Hajjar et al. LV overload was produced by coarctation of the ascending aorta immediately after inoculation of the heart with adenovirus. Two weeks after the procedure, the left ventricular weight/body weight ratio (LVW/BW) increased in the AOB+LacZ group in comparison to that in controls. However, LVW/BW was identical in the AOB+p16 group and controls. Histologic analysis revealed that p16INK4a inhibited hypertrophy of cardiac myocytes. These results suggest that G1 cell cycle regulators may restrict cardiac hypertrophy, and offer a novel strategy for the gene therapy of cardiac hypertrophy.
authors.affiliation: Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nozato
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Ono
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Hiroe
authors.forename: M
authors.initials: M
authors.lastname: Sunamori
authors.forename: F
authors.initials: F
authors.lastname: Marum
mesh_terms: D000199:Actins / Q000235:genetics / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D019942:Genes, p16; D015316:Genetic Therapy; D005822:Genetic Vectors; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014162:Transfection
chemical_list: D000199:Actins; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D018844:Cyclin-Dependent Kinases