Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction

J Mol Cell Cardiol. 2011 Jan;50(1):107-16. doi: 10.1016/j.yjmcc.2010.10.023. Epub 2010 Oct 28.

Abstract

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated with TUDCA (50mg/kg/day, p.o.) or vehicle for 5 weeks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed. Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity and protein expression of intracellular Ca(2+) regulatory proteins were measured using (45)Ca(2+) uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lowered systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca(2+) properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decrease in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blotting, Western
  • Calcium / metabolism
  • Cells, Cultured
  • Echocardiography
  • Endoplasmic Reticulum / metabolism*
  • Glucose Tolerance Test
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Obesity / physiopathology*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Taurochenodeoxycholic Acid / pharmacology*

Substances

  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium