Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels

Dong, De-Li; Duan, Yanjun; Guo, Jiqing; Roach, Daniel E.; Swirp, Shauni L; Wang, Li; Lees‐Miller, James P.; Sheldon, Robert S.; Molkentin, Jeffery D.; Duff, Henry J.

doi:10.1016/s0008-6363(02)00661-2

Cited by 62 publications

(55 citation statements)

References 42 publications

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“…Reduced Kv current densities and action potential prolongation are consistent findings in experimental LVH models [3][4][5][6][7][8][9]11 and in failing human hearts. 10,29 The analyses completed here, however, revealed that cellular hypertrophy (increased C m ) is the main factor in determining reductions in I to,f and I K1 densities, because the mean amplitudes of these currents in TAC and sham LV cells were not significantly different.…”

Section: Marionneau Et Al Mechanisms Underlying K ؉ Current Remodelinsupporting

confidence: 80%

“…Several previous studies have described reductions in K ϩ current densities with LVH or heart failure. [5][6][7][8][9][10][11]29 Most of these studies reported 30% to 50% decreases in K ϩ current densities, with cell membrane capacitances increased by approximately the same percentage. Although not reported, it seems likely that K ϩ current amplitudes were also largely unaffected in these previous studies and that increased cell size was the primary determinant of the reductions in K ϩ current densities.…”

Section: Relationship To Previous Studiesmentioning

confidence: 99%

“…3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, [5][6][7] including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.…”

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Left Ventricular Hypertrophy

Ebert¹

2005

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Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.

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Section: Marionneau Et Al Mechanisms Underlying K ؉ Current Remodelinsupporting

confidence: 80%

Section: Relationship To Previous Studiesmentioning

confidence: 99%

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confidence: 99%

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Left Ventricular Hypertrophy

Ebert¹

2005

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“…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).…”

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“…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).…”

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

Somers

Beck²,

Lees‐Miller³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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