Defective calcium inactivation causes long QT in obese insulin-resistant rat

Details

• Personal Author:
  Castranova, Vincent ; Frisbee JC ; Huang J ; Kan H ; Lin Y-C ; Yu H-G
• Description:
  The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (ICaL) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca2+ influx. The current density of ICaL was reduced in OZR, whereas the threshold activation and the current-voltage relationship of ICaL were not significantly altered. L-type Ba2+ current (IBaL) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of IBaL in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of CavB2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of ICaL and IBaL, 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients. [Description provided by NIOSH]
• Subjects:
  Calcium Compounds Cardiovascular Diseases Cardiovascular System Laboratories Occupational Health Safety
• Keywords:
  Action Potential Author Keywords: Obesity Calcium-compounds Calmodulin Cardiac-function Cardiovascular-system Cardiovascular-system-disease Cardiovascular-system-disorders Diseases Heart Insulin Resistance L-type Calcium Current Laboratory-animals Long QT Physiological-effects Physiological-function Weight-factors

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• ISSN:
  0363-6135
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  302
• Issue:
  4
• NIOSHTIC Number:
  nn:20040368
• Citation:
  Am J Physiol Heart Circ Physiol 2011 Dec; 302(4):H1013-H1022
• Contact Point Address:
  H.-G. Yu, Center for Cardiovascular and Respiratory Sciences, Dept. of Physiology and Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia Univ., Morgantown, WV 26056
• Email:
  hyu@hsc.wvu.edu
• Federal Fiscal Year:
  2012
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Physiology: Heart and Circulatory Physiology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4807620430da8a18654910eb52cbfefba94d1f2ff9a2e2742e7a8237e60f723093b818b15c7f93b973382f98a8c0b1f5e3b216d33c988a6bf7b9cce31e62b79e
• Download URL:
  https://stacks.cdc.gov/view/cdc/193271/cdc_193271_DS1.pdf
• File Type:
  [PDF - 2.11 MB ]