Amplified pathogenic actions of angiotensin II in cysteine-rich LIM-only protein 4-negative mouse hearts

FASEB J. 2017 Apr;31(4):1620-1638. doi: 10.1096/fj.201601186. Epub 2017 Jan 30.

Abstract

LIM domain proteins have been identified as essential modulators of cardiac biology and pathology; however, it is unclear which role the cysteine-rich LIM-only protein (CRP)4 plays in these processes. In studying CRP4 mutant mice, we found that their hearts developed normally, but lack of CRP4 exaggerated multiple parameters of the cardiac stress response to the neurohormone angiotensin II (Ang II). Aiming to dissect the molecular details, we found a link between CRP4 and the cardioprotective cGMP pathway, as well as a multiprotein complex comprising well-known hypertrophy-associated factors. Significant enrichment of the cysteine-rich intestinal protein (CRIP)1 in murine hearts lacking CRP4, as well as severe cardiac defects and premature death of CRIP1 and CRP4 morphant zebrafish embryos, further support the notion that depleting CRP4 is incompatible with a proper cardiac development and function. Together, amplified Ang II signaling identified CRP4 as a novel antiremodeling factor regulated, at least to some extent, by cardiac cGMP.-Straubinger, J., Boldt, K., Kuret, A., Deng, L., Krattenmacher, D., Bork, N., Desch, M., Feil, R., Feil, S., Nemer, M., Ueffing, M., Ruth, P., Just, S., Lukowski, R. Amplified pathogenic actions of angiotensin II in cysteine-rich LIM-only protein 4 negative mouse hearts.

Keywords: BNP; CRP4; Crip1; cGMP; cardiac hypertrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin II / pharmacology
  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Heart / drug effects
  • Heart / growth & development
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Zebrafish
  • alpha-Defensins / genetics*
  • alpha-Defensins / metabolism

Substances

  • Carrier Proteins
  • Crip1 protein, mouse
  • LIM Domain Proteins
  • alpha-Defensins
  • cryptdin 4, mouse
  • Angiotensin II
  • Cyclic GMP