Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure

Meguro, Tomomi; Hong, Chull; Asai, Kuniya; Takagi, Gen; McKinsey, Timothy A.; Olson, Eric N.; Vatner, Stephen F.

doi:10.1161/01.res.84.6.735

Cited by 166 publications

(130 citation statements)

References 28 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.

193

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.

193

133

View full text Add to dashboard Cite

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“…The effectiveness of the CsA treatment could depend on the duration of the hypertrophic stimulus. In mice with transverse aortic constriction, pressure overload-induced cardiac hypertrophy was also insensitive to CsA treatment (18,20,21). However, constriction of the aortic arch does not activate the renin-angiotensin system (25).…”

Section: Discussionmentioning

confidence: 99%

“…Calcineurin Assay-Assay was performed essentially as described (21). Briefly, hearts or cultured cardiomyocytes were homogenized in 1 ml of assay buffer (0.1 M MOPS, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, containing a protease inhibitor mixture (Complete; Roche Molecular Biochemicals)).…”

Section: Methodsmentioning

confidence: 99%

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Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension

Murat¹,

Pellieux²,

Brunner

et al. 2000

Journal of Biological Chemistry

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Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca 2؉ /calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.

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“…Transverse aortic banding or sham operation was performed in 4-to 6-mo-old homozygous AC5 Ϫ/Ϫ and WT littermates. The method of imposing pressure overload in mice has been described (26). Mice were anesthetized i.p.…”

Section: Methodsmentioning

confidence: 99%

Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload

Okumura¹,

Takagi²,

Kawabe³

et al. 2003

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

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185

164

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The sympathetic nervous system is designed to respond to stress. Adenylyl cyclase (AC) is the keystone of sympathetic transmission, yet its role in response to acute overload in the heart or in the pathogenesis of heart failure is controversial. We examined the effects of pressure overload, induced by thoracic aortic banding, in mice in which type 5 AC, a major cardiac AC isoform, was disrupted (AC5 ؊/؊ ). Left ventricular weight͞tibial length ratio (LVW͞TL) was not different between the WT and AC5 ؊/؊ at baseline and increased progressively and similarly in both groups at 1 and 3 wk after aortic banding. However, LV ejection fraction (LVEF) fell in WT at 3 wk after banding (from 70 ؎ 2.8 to 57 ؎ 3.9%, P < 0.05), and this decrease was associated with LV dilatation, indicating incipient cardiac failure. In contrast, AC5 ؊/؊ mice did not exhibit a fall in LVEF from 74 ؎ 2.2%. The number of apoptotic myocytes was similar at baseline, but it increased roughly 4-fold in WT at both 1 and 3 wk after banding, and significantly less, P < 0.05, in AC5 ؊/؊ . Importantly, the increase in apoptosis occurred before the decline in LVEF in WT. The protective mechanism seems to involve Bcl-2, which was up-regulated significantly more in AC5 ؊/؊ mice with pressure overload. Our findings suggest that limiting type 5 AC plays a protective role in response to pressure overload and the development of heart failure, potentially through limiting the incidence of myocardial apoptosis.

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Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure

Cited by 166 publications

References 28 publications

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension

Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload

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