Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning

Endocrinology. 2006 Oct;147(10):4569-77. doi: 10.1210/en.2006-0297. Epub 2006 Jun 22.


Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Androgen Receptor Antagonists
  • Animals
  • Blotting, Western
  • Body Weight / drug effects
  • Cell Hypoxia / physiology
  • Cell Survival / drug effects
  • DNA-Binding Proteins / physiology
  • HSP70 Heat-Shock Proteins / biosynthesis*
  • Heart Function Tests
  • Heat Shock Transcription Factors
  • In Vitro Techniques
  • Ischemic Preconditioning, Myocardial*
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Myocardial Infarction / pathology
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Orchiectomy
  • Organ Size / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Testosterone / pharmacology
  • Testosterone / physiology*
  • Transcription Factors / physiology


  • Androgen Receptor Antagonists
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Transcription Factors
  • Testosterone
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • L-Lactate Dehydrogenase