p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling

• Published in: Peptides (New York, N.Y. : 1980) Vol. 83; pp. 38 - 48
• Main Authors: Hauck, Ludger, Grothe, Daniela, Billia, Filio
• Format: Journal Article
• Language: English
• Published: United States 01.09.2016
• Subjects: Angiotensin II - administration & dosage; Angiotensin II - metabolism; Animals; Cardiomegaly - genetics; Cardiomegaly - physiopathology; Cardiomegaly - therapy; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Gene Expression Regulation - genetics; Heart - growth & development; Heart - physiopathology; Heart Failure - genetics; Heart Failure - physiopathology; Heart Failure - therapy; Humans; Mice; Mice, Knockout; Oncogene Protein v-akt - genetics; Proto-Oncogene Proteins c-myc - genetics; Retinoblastoma Protein - genetics; Heart failure; Cardiac hypertrophy; Cdk; p21; Cyclin D2; Cardiac fibrosis; p27; Myc; Angiotensin; Cell cycle; Cdkn1a; Retinoblastoma; Cdkn1b
• ISSN: 1873-5169
• DOI: 10.1016/j.peptides.2016.07.003

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.