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

Abstract

HJ. iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin. Am J Physiol Heart Circ Physiol 295: H1122-H1131, 2008. First published July 11, 2008 doi:10.1152/ajpheart.00386.2008.-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 Ϫ/Ϫ and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS Ϫ/Ϫ mice had improved systolic performance (P Ͻ 0.001) and less heart block (P Ͻ 0.0001); larger sodium current density and lower serum TNF-␣ levels (P Ͻ 0.03); and less apoptosis (P Ͻ 0.01) resulting in improved survival (P Ͻ 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS Ϫ/Ϫ mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BMderived 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. heart block; sodium current; sudden death; inducible nitric oxide synthase; transgenic overexpression of calcineurin TRANSGENIC OVEREXPRESSION of constitutively active calcineurin (CN/Tg) in cardiac myocytes results in profound concentric hypertrophy followed by ventricular dilatation, interstitial fibrosis, heart failure, and eventually sudden cardiac death (13,26,32,33,40). The sudden deaths relate to ion channelopathies, which are downstream consequences of abnormalities of calcium homeostasis (17) and an inflammatory process (6, 10, 27, 36).Previous studies indicate that inducible nitric oxide (NO) synthase (iNOS) is a downstream target of calcineurin (12,19,36,44,45). The regulation of the iNOS gene promoter by calcineurin has been reported (36). LPS-induced iNOS expression in the heart was abrogated by the pharmacological inhibition of calcineurin (36). Similarly, LPS induced the expression of iNOS in wild-type (WT) hearts but not in the calcineurin A␤ knockout hearts (36). Reciprocally, the overexpression of constitutively active calcineurin in isolated cardiomyocytes caused the dephosphorylation and nuclear accumulation of the transcription factor family originally defined as nuclear factor of activated T-cells (NFAT)c1 and induced strong iNOS expression (36). In addition, chromatin immunoprecipitation confirmed the calcineurin-dependent binding of NFATc1 to the iNOS promoter (36). These data are co...

Protein Kinase Cε-Calcineurin Cosignaling Downstream of Toll-Like Receptor 4 Downregulates Fibrosis and Induces Wound Healing Gene Expression in Cardiac Myofibroblasts

“…Furthermore, transgenic mice overexpressing this truncated form of CnA␣ (CN-TG) develop cardiac hypertrophy, adverse remodeling, heart failure, and sudden death (31,44). Therefore, we examined the expression of COX-2 and connective tissue growth factor (CTGF) as an early marker of fibrosis remodeling in CN-TG hearts compared to nontransgenic (NTG) controls.…”

“…Constitutive activation of CnA␣ has also been show to be associated with heart failure in humans (43). Furthermore, transgenic mice harboring the same catalytic fragment in a myocardially restricted manner develop adverse cardiac remodeling, heart failure, and sudden death (31,44). This phenotype is rescued by crossing into a transgenic mouse line expressing the endogenous calcineurin repressor myocte-enriched calcineurin inhibitor protein 1 (MCIP-1) (61).…”

Study of Anti-Ischemic Effect of Afobazole in Experimental Myocardial Infarction

“…This enzyme is now regarded as one of the main mediators of ischemic damage to cardiomyocytes. Hyperproduction of iNOS is destructive for cardiomyocytes and initiates dysfunction of the left ventricle, causing its postischemic remodeling and increasing the risk of sudden coronary death [10]. Presumably, inhibition of iNOS activity by σ 1 receptor agonists stimulates the synthesis of constitutive nitroxi de synthase (cNOS) by the ischemic myocardium.…”

Sabiporide Reduces Ischemia-Induced Arrhythmias and Myocardial Infarction and Attenuates ERK Phosphorylation and iNOS Induction in Rats

“…Increased iNOS expression is a component of the immune response and has been demonstrated in cardiomyocytes in ischemia-reperfusion, septic shock, myocarditis, transplant rejection, dilated cardiomyopathy, and heart failure [32–34]. Studies indicate that nitric oxide produced by iNOS is cardiotoxic in that it suppresses myocardial contractility and increases myocyte apoptosis and mortality [33, 35, 36].…”