Muscle ring finger 1 mediates cardiac atrophy in vivo

Monte Willis, Mauricio Rojas, Luge Li, Craig H. Selzman, Ru Hang Tang, William E. Stansfield, Jessica E. Rodriguez, David J. Glass, Cam Patterson

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1 -/-mice decreased ∼70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by β-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1 -/- and wild-type hearts after TAC release. In the second model, MuRF1 -/-mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

Fingerprint

Cardiomegaly
Fingers
Atrophy
Muscles
Constriction
Dexamethasone
Cardiac Myocytes
Therapeutic Human Experimentation
Heart-Assist Devices
Myosin Heavy Chains
Muscle Proteins
Brain Natriuretic Peptide
Aortic Valve Stenosis
Transcriptional Activation
Smooth Muscle
Actins
Myocardium
Heart Failure
Hypertension
Gene Expression

Keywords

  • Cardiac atrophy
  • Cardiac hypertrophy
  • Left ventricular assist device
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Muscle ring finger 1 mediates cardiac atrophy in vivo. / Willis, Monte; Rojas, Mauricio; Li, Luge; Selzman, Craig H.; Tang, Ru Hang; Stansfield, William E.; Rodriguez, Jessica E.; Glass, David J.; Patterson, Cam.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 296, No. 4, 01.04.2009.

Research output: Contribution to journalArticle

Willis, M, Rojas, M, Li, L, Selzman, CH, Tang, RH, Stansfield, WE, Rodriguez, JE, Glass, DJ & Patterson, C 2009, 'Muscle ring finger 1 mediates cardiac atrophy in vivo', American Journal of Physiology - Heart and Circulatory Physiology, vol. 296, no. 4. https://doi.org/10.1152/ajpheart.00660.2008
Willis, Monte ; Rojas, Mauricio ; Li, Luge ; Selzman, Craig H. ; Tang, Ru Hang ; Stansfield, William E. ; Rodriguez, Jessica E. ; Glass, David J. ; Patterson, Cam. / Muscle ring finger 1 mediates cardiac atrophy in vivo. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 296, No. 4.
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