Calcineurin Plays a Critical Role in the Development of Pressure Overload–Induced Cardiac Hypertrophy

Calcineurin is a Ca2؉ /calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.Terminally differentiated cardiac myocytes develop hypertrophy in response to stressful stimuli. The resulting increases in left ventricular (LV) 1 wall thickness serve to normalize wall stress and diminish myocardial oxygen consumption. Salutary effects on energy metabolism, however, are counterbalanced by heightened risk of cardiovascular morbidity and mortality (1). Prominent among these is increased risk of heart failure. Calcineurin is a Ca 2ϩ /calmodulin-activated cytoplasmic protein phosphatase (PP2B) that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation (2). A number of groups have investigated the importance of calcineurin signaling in models of in vivo hypertrophy (reviewed in Ref. 2). Although results have been varied, most reports relied on pharmacological inhibition of calcineurin using either cyclosporin A (CsA) or FK-506. Although CsA is a specific inhibitor of calcineurin, CsA has multiple effects on cellular signaling, including altered expression of the cardiac Na ϩ -Ca 2ϩ exchanger (3) and increased concentrations of intracellular Ca 2ϩ (4). Calcineurin is a ubiquitous protein, and systemic CsA has effects on other, noncardiac organ systems.MCIP1 (myocyte-enriched calcineurin-interacting protein) is a recently described (5, 6) protein that is preferentially expressed in striated muscle and that directly binds to the catalytic subunit (CnA) of the calcineurin holoenzyme. MCIP1 binding to CnA inhibits activating eff...

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“…neural) effects of calcineurin suppression. Similar results were recently reported using other transgenic approaches (14,15).…”

Section: Discussionsupporting

confidence: 91%

Targeted Inhibition of Calcineurin in Pressure-overload Cardiac Hypertrophy

Hill¹,

Rothermel²,

Yoo³

et al. 2002

Journal of Biological Chemistry

113

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“…Histological analysis of the heart tissue was performed according to previously described methods (16). Ventricular sections were stained with H&E for routine histological examination.…”

Section: Animalmentioning

confidence: 99%

“…Aortic banding. Suprarenal aortic banding was produced as previously described (16). Briefly, under ketamine anesthesia (100 mg/kg, i.p.…”

Section: Introductionmentioning

confidence: 99%

Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway

Yang

Tan

et al. 2010

Mol Med Rep

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Abstract. calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (nFaT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective β blocker/α-1 blocker carvedilol or the selective β-1 blocker metoprolol, but not the selective α-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.

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“…Gain-and loss-of-function studies in genetically altered mice and cultured cardiomyocytes have demonstrated the sufficiency and necessity of calcineurin to regulate pathological cardiac hypertrophy (5)(6)(7)(8)(9)(10)(11)(12). In contrast, in vivo confirmation about the involvement of its direct downstream transcriptional effectors in the heart is still incompletely resolved.…”

mentioning

confidence: 99%

NFATc2 Is a Necessary Mediator of Calcineurin-dependent Cardiac Hypertrophy and Heart Failure

Bourajjaj

Armand

Martins

et al. 2008

Journal of Biological Chemistry

141

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One major intracellular signaling pathway involved in heart failure employs the phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T-cells (NFAT). In vivo evidence for the involvement of NFAT factors in heart failure development is still ill defined. Here we reveal that nfatc2 transcripts outnumber those from other nfat genes in the unstimulated heart by severalfold. Transgenic mice with activated calcineurin in the postnatal myocardium crossbred with nfatc2-null mice revealed a significant abrogation of calcineurin-provoked cardiac growth, indicating that NFATc2 plays an important role downstream of calcineurin and validates the original hypothesis that calcineurin mediates myocyte hypertrophy through activation of NFAT transcription factors. In the absence of NFATc2, a clear protection against the geometrical, functional, and molecular deterioration of the myocardium following biomechanical stress was also evident. In contrast, physiological cardiac enlargement in response to voluntary exercise training was not affected in nfatc2-null mice. Combined, these results reveal a major role for the NFATc2 transcription factor in pathological cardiac remodeling and heart failure.Heart failure, or the inability of the heart to meet hemodynamic demands, represents the end stage of various forms of cardiac disease. In the Western world, the prevalence and incidence of heart failure are increasing steadily, and heart failure is now the leading cause of hospitalization in the elderly. The leading cause of heart failure is left ventricular hypertrophy, defined as an increase in heart size without a change in myocyte number, because chronically hypertrophied hearts remodel and dilate (1, 2). Conversely, not all forms of cardiac hypertrophy are necessarily pathological, as athletic conditioning can stimulate heart growth without deleterious consequences (3). Hence, a better understanding of the mechanisms underlying pathological versus adaptive hypertrophic growth of the myocardium is key to develop preventative measures and therapeutics for heart failure patients (4).Gain-and loss-of-function studies in genetically altered mice and cultured cardiomyocytes have demonstrated the sufficiency and necessity of calcineurin to regulate pathological cardiac hypertrophy (5-12). In contrast, in vivo confirmation about the involvement of its direct downstream transcriptional effectors in the heart is still incompletely resolved. Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT) 2 transcription factor family (13), allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to regulate calcineurin-responsive target genes. The ventricular cardiomyocyte contains all four calcineurin-sensitive NFATc isoforms, NFATc1 (NFATc), NFATc2 (NFATp), NFATc3 (NFAT4), and NFATc4 (NFAT3) (14, 15), and expression of dominant-negative forms of NFAT virtually abolishes calcineurin-mediated hypertrophy in cultured cardiomyocytes (14, 16). I...

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Calcineurin Plays a Critical Role in the Development of Pressure Overload–Induced Cardiac Hypertrophy

Abstract: These results suggest that calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy.

Cited by 110 publications

References 24 publications

Targeted Inhibition of Calcineurin in Pressure-overload Cardiac Hypertrophy

Targeted Inhibition of Calcineurin in Pressure-overload Cardiac Hypertrophy

Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway

NFATc2 Is a Necessary Mediator of Calcineurin-dependent Cardiac Hypertrophy and Heart Failure

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