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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes

Published on: September 18, 2017

Doxorubicin cardiac dysfunction: effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine

Richard D Olson1, Hervé A Gambliel, Robert E Vestal

  • 1Pharmacology and Gerontology Research Unit, Veteran's Affairs Medical Center, 500 W. Fort St., Boise, ID 83702, USA. rolson49@aol.com

Cardiovascular Toxicology
|October 26, 2005
PubMed

Insights

Doxorubicin-induced cardiomyopathy in rabbits impairs heart contractility by reducing key calcium handling proteins in the sarcoplasmic reticulum (SR). This SR dysfunction is linked to decreased triiodothyronine (T3) levels.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Doxorubicin is a widely used chemotherapy agent.
  • Doxorubicin can cause cardiotoxicity, leading to heart failure.
  • The precise mechanisms of doxorubicin-induced cardiotoxicity are not fully understood.

Purpose of the Study:

  • To investigate the relationship between calcium handling protein alterations and contractile dysfunction in a rabbit model of chronic doxorubicin cardiomyopathy.
  • To explore the role of sarcoplasmic reticulum (SR) dysfunction in doxorubicin-induced cardiotoxicity.
  • To examine the potential influence of triiodothyronine (T3) levels on this process.

Main Methods:

  • New Zealand white rabbits received chronic doxorubicin or saline injections.
  • Left ventricular gene transcript and protein levels of key calcium handling proteins were assessed.
  • Cardiac contractility and [3H]-ryanodine binding to RYR2 were measured.
  • Serum T3 concentrations were analyzed.

Main Results:

  • Doxorubicin treatment significantly decreased protein levels of SERCA2 and RYR2, as well as RYR2 mRNA and Bmax.
  • Left-ventricular fractional shortening significantly correlated with SERCA2, RYR2 protein and mRNA levels, and RYR2 Bmax.
  • Atrial preparations from doxorubicin-treated rabbits showed diminished contractility, indicating SR dysfunction.
  • Serum free T3 concentrations were reduced in doxorubicin-treated rabbits.

Conclusions:

  • Chronic doxorubicin administration induces SR-dependent contractile dysfunction in rabbits.
  • Decreased expression and function of SERCA2 and RYR2 contribute to doxorubicin-induced cardiomyopathy.
  • Reduced serum T3 levels may play a role in the development of doxorubicin-induced cardiac dysfunction.

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