title: p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling.
abstract: The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart.
authors.affiliation: Toronto General Research Institute, 100 College St., Toronto, Ontario, M5G 1L7, Canada. Electronic address: lhauck@uhnres.utoronto.ca.
authors.forename: Ludger
authors.initials: L
authors.lastname: Hauck
authors.affiliation: Toronto General Research Institute, 100 College St., Toronto, Ontario, M5G 1L7, Canada. Electronic address: dgrothe@uhnres.utoronto.ca.
authors.forename: Daniela
authors.initials: D
authors.lastname: Grothe
authors.affiliation: Toronto General Research Institute, 100 College St., Toronto, Ontario, M5G 1L7, Canada; Division of Cardiology, University Health Network (UHN), 200 Elizabeth St., Toronto, Ontario, M5G 2C4, Canada; Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Canada; Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5G 1A8, Canada. Electronic address: phyllis.billia@uhn.ca.
authors.forename: Filio
authors.initials: F
authors.lastname: Billia
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006321:Heart / Q000254:growth & development / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D000804:Angiotensin II; D051058:Oncogene Protein v-akt
keywords: Angiotensin; Cardiac fibrosis; Cardiac hypertrophy; Cdk; Cdkn1a; Cdkn1b; Cell cycle; Cyclin D2; Heart failure; Myc; Retinoblastoma; p21; p27