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

Shimoyama, Masaki; Hayashi, Doubun; Takimoto, Eiki; Zou, Yunzeng; Oka, Tôru; Uozumi, Hiroki; Kudoh, Sumiyo; Shibasaki, Futoshi; Yazaki, Yoshio; Nagai, Ryozo; Komuro, Issei

doi:10.1161/01.cir.100.24.2449

Cited by 133 publications

(107 citation statements)

References 44 publications

(51 reference statements)

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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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“…Calcineurin has been indirectly implicated in the development of cardiac fibrosis [14,34,35], and transgenic mice expressing constitutively active calcineurin in cardiomyocytes not only developed cardiac hypertrophy, but a concomitant accumulation of collagen deposits surrounding the degenerating 14 cardiomyocytes [14,34]. Also, in vivo treatment with pharmacological inhibitors of calcineurin could limit the pressure overload-induced cardiac fibrosis [34].…”

Section: Discussionmentioning

confidence: 99%

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

Herum

Lunde

Skrbic

et al. 2013

Journal of Molecular and Cellular Cardiology

113

101

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“…Adult rats (2-3 month-old) were anesthetized with ketamine (4 mg/kg IM) and xylazine (50 mg/kg IM), as previously described [10]. The heart was quickly removed and retrogradely perfused under constant pressure (60 mm Hg) at 37°C for ~4 min with a Ca 2+ -free buffer containing (in mM) (130)NaCl, (5)KCl, (5)MgSO 4 , (21)glucose, (1)NaH 2 PO 4 , (20)taurine, (5)creatine, (5)Na pyruvate, (23)HEPES.…”

Section: Culture Of Adult Rat Cardiomyocytesmentioning

confidence: 99%

Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ

Ding¹,

Qin²,

He³

et al. 2007

Journal of Molecular and Cellular Cardiology

127

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Adiponectin is a protein hormone involved in maintaining energy homeostasis in metabolically active tissues. It enhances glucose and lipid metabolism via activation of AMP-dependent kinase (AMPK) in skeletal muscle and liver. Energy homeostasis is vital for the heart to work as a pump. In this study, we investigated whether adiponectin and its receptors are expressed in adult ventricular cardiomyocytes. We observed adiponectin transcript and protein in cultured ventricular cardiomyocytes isolated from adult rat, by quantitative real-time PCR, ELISA assays, Western blots, and immunofluorescent staining. In addition, we detected adiponectin receptor (AdipoR1 and AdipoR2) expression in the heart. AdipoR1 was expressed in rat myocardium at a level of about 50% of that in skeletal muscle; whereas adipoR2 was expressed at a similar level to that in liver. Rosiglitazone, a Peroxisome proliferator activated receptor γ (PPARγ) activator, substantially elevated expression of adiponectin in cultured cardiomyocytes and its secretion into cultured media. Rosiglitazone also increased adipoR1 and adipoR2 expression in cardiomyocytes. Treatment of recombinant globular adiponectin in cultured cardiomyocytes increased fatty acid oxidation and glucose uptake via activation of AMPK, suggesting a role for adiponectin in cardiac energy metabolism. Together, these data establish the existence of a local cardiac-specific adiponectin system that is regulated by PPARγ. Moreover, these findings indicate a role for adiponectin on normal myocardial energy homeostasis, in part, through the activation of AMPK.

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

Cited by 133 publications

References 44 publications

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ

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