Calcineurin Is Activated in Rat Hearts With Physiological Left Ventricular Hypertrophy Induced by Voluntary Exercise Training

Eto, Yoko; Yonekura, Katsunori; Sonoda, Makoto; Arai, Naoto; Sata, Masataka; Sugiura, Seiryo; Takenaka, Katsu; Gualberto, Antonio; Hixon, Mary L.; Wagner, Mark W.; Aoyagi, Takaaki

doi:10.1161/01.cir.101.18.2134

Cited by 68 publications

(55 citation statements)

References 19 publications

(19 reference statements)

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“…This is accompanied by an increase in calcineurin phosphatase activity. Our results are in line with 2 recent studies on rat myocardium that describe increased calcineurin activity in physiological hypertrophy 10 and at the beginning of pressure-overload hypertrophy, 6 although neither group was investigating proteolysis of calcineurin in these animals.…”

Section: Discussionsupporting

confidence: 92%

Calcineurin in Human Heart Hypertrophy

et al. 2002

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Background-In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. Methods and Results-We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reversetranscription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. Conclusions-Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain.Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

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Section: Discussionsupporting

confidence: 92%

Calcineurin in Human Heart Hypertrophy

et al. 2002

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“…The results of the present study support an increasing body of literature consisting of 13 reports at present which demonstrate a partial or complete inhibition of cardiac hypertrophy or heart failure by using cyclosporine and͞or FK506 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(41)(42)(43). However, such reports remain controversial for a number of reasons.…”

Section: Discussionsupporting

confidence: 81%

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Windt

Lim

Bueno

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

190

128

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The Ca 2؉ -calmodulin-activated Ser͞Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor of activated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signaling pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or genetic-based inhibitory strategies. In this regard, we have generated Tg mice expressing the calcineurin inhibitory domains of Cain͞Cabin-1 and A-kinase anchoring protein 79 specifically in the heart. ⌬Cain and ⌬A-kinase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin activity and reduced hypertrophy in response to catecholamine infusion or pressure overload. In a second approach, adenoviral-mediated gene transfer of ⌬Cain was performed in the adult rat myocardium to evaluate the effectiveness of an acute intervention and any potential species dependency. ⌬Cain adenoviral gene transfer inhibited cardiac calcineurin activity and reduced hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin as an important mediator of the cardiac hypertrophic response in vivo.C ardiac hypertrophy is broadly defined as an adaptive enlargement of the myocardium characterized by the growth of individual cardiac myocytes rather than an increase in cell number. Whereas cardiac hypertrophy is a beneficial response that temporarily augments output, sustained hypertrophy often becomes maladaptive and is a leading predictor of future heart failure (1, 2). To understand the molecular mechanisms that underlie adaptive and maladaptive cardiac hypertrophy, investigation has centered around a characterization of the intracellular signal transduction pathways that promote cardiac myocyte growth (3, 4).One such intracellular signaling pathway involves the calciumcalmodulin, Ser͞Thr protein phosphatase calcineurin (PP2B). Sustained elevations in intracellular calcium concentration, in association with calmodulin, directly activate calcineurin phosphatase activity leading to the dephosphorylation and nuclear translocation of a family of transcription factors known as nuclear factor of activated T cells (5, 6).A role for calcineurin and nuclear factor of activated T cells as regulators of cardiac hypertrophy was recently identified (7). Transgenic (Tg) mice expressing an activated calcineurin or a constitutively nuclear nuclear factor of activated T cells c4 factor in the heart demonstrated profound hypertrophy that rapidly progressed to heart failure (7). In vitro, adenoviral-mediated gene transfer of activated calcineurin also promoted hypertrophic growth of neonatal cardiac myocytes (8). Treatment of cultured cardiomyocytes with the calcineurin inhibitory agents cyclosporine A (CsA) or FK506 blocked agonist-induced hypertrop...

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“…Several studies demonstrated an increase in calcineurin activity in pressure-overload hypertrophy (18)(19)(20)(21). However, a decrease in calcineurin protein expression in the hypertrophic heart has also been reported (22).…”

Section: Discussionmentioning

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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Calcineurin Is Activated in Rat Hearts With Physiological Left Ventricular Hypertrophy Induced by Voluntary Exercise Training

Cited by 68 publications

References 19 publications

Calcineurin in Human Heart Hypertrophy

Calcineurin in Human Heart Hypertrophy

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

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

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