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The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure.

Publication ,  Journal Article
Beak, JY; Kang, HS; Huang, W; Myers, PH; Bowles, DE; Jetten, AM; Jensen, BC
Published in: Am J Physiol Heart Circ Physiol
January 1, 2019

The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the "staggerer" (RORαsg/sg) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORαsg/sg and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORαsg/sg mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr705), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.

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Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

January 1, 2019

Volume

316

Issue

1

Start / End Page

H186 / H200

Location

United States

Related Subject Headings

  • STAT3 Transcription Factor
  • Rats, Sprague-Dawley
  • Rats
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Mitochondria, Heart
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
 

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Beak, J. Y., Kang, H. S., Huang, W., Myers, P. H., Bowles, D. E., Jetten, A. M., & Jensen, B. C. (2019). The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol, 316(1), H186–H200. https://doi.org/10.1152/ajpheart.00531.2018
Beak, Ju Youn, Hong Soon Kang, Wei Huang, Page H. Myers, Dawn E. Bowles, Anton M. Jetten, and Brian C. Jensen. “The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure.Am J Physiol Heart Circ Physiol 316, no. 1 (January 1, 2019): H186–200. https://doi.org/10.1152/ajpheart.00531.2018.
Beak JY, Kang HS, Huang W, Myers PH, Bowles DE, Jetten AM, et al. The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H186–200.
Beak, Ju Youn, et al. “The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure.Am J Physiol Heart Circ Physiol, vol. 316, no. 1, Jan. 2019, pp. H186–200. Pubmed, doi:10.1152/ajpheart.00531.2018.
Beak JY, Kang HS, Huang W, Myers PH, Bowles DE, Jetten AM, Jensen BC. The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H186–H200.

Published In

Am J Physiol Heart Circ Physiol

DOI

EISSN

1522-1539

Publication Date

January 1, 2019

Volume

316

Issue

1

Start / End Page

H186 / H200

Location

United States

Related Subject Headings

  • STAT3 Transcription Factor
  • Rats, Sprague-Dawley
  • Rats
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Mitochondria, Heart
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice