Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats

Sakata, Yasushi; Masuyama, Tohru; Yamamoto, Keiji; Nishikawa, Nagahiro; Yamamoto, Hideyuki; Kondo, Hiroya; Ono, Keiko; Otsu, Kinya; Kuzuya, Tsunehiko; Miwa, Takeshi; Takeda, Hiroshi; Miyamoto, Eishichi; Hori, Masatsugu

doi:10.1161/01.cir.102.18.2269

Cited by 75 publications

(54 citation statements)

References 15 publications

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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.

192

133

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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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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.

192

133

View full text Add to dashboard Cite

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“…For example, some reports have indicated that cyclosporine could actually be protective against reperfusion-associated dysrhythmias (16). Other reports have indicated that cyclosporine may also be protective against the development of left ventricular hypertrophy and cardiac enlargement (17), although tacrolimus appears to have at least an equivalent effect (18). Clinically important interactions between cyclosporine and amiodarone, which the present study could not measure, have been reported (19,20).…”

Section: Discussionmentioning

confidence: 66%

Hospitalized Atrial Fibrillation After Renal Transplantation in the United States

Abbott¹,

Reynolds²,

Taylor

et al. 2003

American Journal of Transplantation

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“…A number of recent studies have investigated calcineurin activity in various animal models of cardiac hypertrophy (1,16,18,19). Several studies demonstrated an increase in calcineurin activity in pressure-overload hypertrophy (18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac hypertrophy is a leading cause of the development of congestive heart failure and sudden death in humans (1).…”

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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Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats

Cited by 75 publications

References 15 publications

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Hospitalized Atrial Fibrillation After Renal Transplantation in the United States

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

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