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

Peptides. 2016 Sep:83:38-48. doi: 10.1016/j.peptides.2016.07.003. Epub 2016 Jul 30.

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.

Keywords: Angiotensin; Cardiac fibrosis; Cardiac hypertrophy; Cdk; Cdkn1a; Cdkn1b; Cell cycle; Cyclin D2; Heart failure; Myc; Retinoblastoma; p21; p27.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Retinoblastoma Protein
  • Angiotensin II
  • Oncogene Protein v-akt

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