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Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes

Rita M Maalouf1, Assaad A Eid, Yves C Gorin

  • 1Dept. of Medicine, Division of Cardiology, Univ. of Texas Health Science Center, San Antonio, TX 78229-3900, USA. rita.maalouf@ndu.edu.lb

American Journal of Physiology. Cell Physiology
|October 28, 2011
PubMed

Insights

Diabetic cardiomyopathy involves oxidative stress. This study shows NADPH oxidase Nox4 generates reactive oxygen species (ROS) contributing to this condition, suggesting Nox4 as a therapeutic target.

Area of Science:

  • Cardiovascular Research
  • Oxidative Stress Biology
  • Molecular Cardiology

Background:

  • Diabetic cardiomyopathy is a significant complication of diabetes mellitus.
  • Oxidative stress, driven by reactive oxygen species (ROS), plays a critical role in its pathogenesis.
  • The specific sources of ROS in early diabetic cardiomyopathy require further elucidation.

Purpose of the Study:

  • To investigate the role of NADPH oxidase Nox4 as a primary source of ROS in the development of diabetic cardiomyopathy.
  • To determine if inhibiting Nox4 can ameliorate cardiac dysfunction and structural changes in diabetic rats.
  • To examine the direct effect of high glucose on Nox4 expression and cardiac injury in vitro.

Main Methods:

  • Administration of antisense (AS) or sense (S) oligonucleotides targeting Nox4 in streptozotocin-induced diabetic rats.
  • Measurement of NADPH oxidase activity, ROS generation, and Nox4 expression in cardiac tissue.
  • Assessment of molecular markers for hypertrophy and myofibrosis (e.g., fibronectin, collagen).
  • Evaluation of cardiac contractility in treated and untreated diabetic rats.
  • In vitro studies using cultured cardiac myocytes exposed to high glucose and Nox4 inhibition.

Main Results:

  • Diabetic rats exhibited increased NADPH oxidase activity, ROS generation, and Nox4 expression in the left ventricle.
  • Markers of cardiac hypertrophy and myofibrosis were elevated in diabetic rats.
  • Administration of AS Nox4, but not S Nox4, attenuated these pathological changes and preserved cardiac contractility.
  • High glucose exposure in cultured cardiac myocytes increased Nox4 expression and markers of injury, effects reversed by dominant-negative Nox4.

Conclusions:

  • Nox4 is a significant source of ROS in the diabetic heart.
  • Nox4-derived ROS contribute to the development of early-stage diabetic cardiomyopathy.
  • Targeting Nox4 represents a potential therapeutic strategy for preventing or treating diabetic cardiomyopathy.

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