iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin.

Abstract

Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS(-/-) and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS(-/-) mice had improved systolic performance (P < 0.001) and less heart block (P < 0.0001); larger sodium current density and lower serum TNF-alpha levels (P < 0.03); and less apoptosis (P < 0.01) resulting in improved survival (P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS(-/-) mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.

• Authors: Julie R Somers, Paul L Beck, James P Lees-Miller, Daniel Roach, Yan Li, J Guo, Steven Loken, Shan Zhan, Lisa Semeniuk, Henry J Duff
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 295 Issue 3 Pg. H1122-H1131 (Sep 2008) ISSN: 0363-6135 [Print] United States
• PMID: 18621856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sodium Channels
• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Calcineurin

Topics

• Animals
• Apoptosis (genetics, physiology)
• Arrhythmias, Cardiac (genetics, physiopathology)
• Calcineurin (genetics, physiology)
• Cardiomegaly (genetics, pathology)
• Cardiomyopathy, Dilated (genetics, pathology)
• Cell Death (physiology)
• Death, Sudden
• Echocardiography
• Enzyme-Linked Immunosorbent Assay
• Heart Block (genetics, physiopathology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Mice, Knockout
• Mice, Transgenic
• Myocytes, Cardiac (enzymology, physiology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (genetics, physiology)
• Sodium Channels (physiology)
• Survival Analysis
• Tumor Necrosis Factor-alpha (metabolism)