Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy

Am J Physiol Gastrointest Liver Physiol. 2020 Mar 1;318(3):G531-G541. doi: 10.1152/ajpgi.00346.2019. Epub 2020 Jan 21.


Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.

Keywords: adrenergic; caveolin; cirrhotic cardiomyopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials
  • Animals
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology
  • Cardiomyopathies / prevention & control
  • Caveolin 3 / genetics
  • Caveolin 3 / metabolism*
  • Disease Models, Animal
  • Heart Rate
  • Isolated Heart Preparation
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / metabolism*
  • Liver Cirrhosis, Biliary / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Pyridines
  • Signal Transduction
  • Time Factors
  • Up-Regulation


  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Cav3 protein, mouse
  • Caveolin 3
  • Pyridines