Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload

Hill, Joseph A.; Karimi, Mohsen; Kutschke, William; Davisson, Robin L.; Zimmerman, Kathy; Wang, Zhengyi; Kerber, Richard E.; Weiß, Robert M.

doi:10.1161/01.cir.101.24.2863

Cited by 283 publications

(250 citation statements)

References 40 publications

(38 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

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“…In parallel with the increase in LVM/BW, mean LV myocyte size, as determined by C m measurements, was increased with TAC, in agreement with previous reports. 8,28 In contrast to these earlier reports, however, there was no evidence that mean LVM/BW or myocyte size continued to increase at longer times (up to 3 months) after TAC. Also, in contrast to the effects on LV cells, there were no differences in mean C m in TAC and sham RV cells, demonstrating that the cellular hypertrophy is specific for the LV.…”

Section: Lvh In Tac Micecontrasting

confidence: 58%

Left Ventricular Hypertrophy

Ebert¹

2005

Easy ECG

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Abstract-Left ventricular hypertrophy (LVH) is associated with electric remodeling and increased arrhythmia risk, although the underlying mechanisms are poorly understood. In the experiments here, functional voltage-gated (Kv) and inwardly rectifying (Kir) K ϩ channel remodeling was examined in a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC). Action potential durations (APDs) at 90% repolarization in TAC LV myocytes and QT c intervals in TAC mice were prolonged. Mean whole-cell membrane capacitance (C m ) was higher, and Key Words: hypertrophy Ⅲ arrhythmia Ⅲ heart failure L eft ventricular hypertrophy (LVH) is an adaptive response of the myocardium to an increase in load. 1 LVH is seen in various disease states including hypertension and myocardial infarction, as well as in valvular and congenital heart diseases. 1 LVH is also observed in physiological states following rigorous, prolonged exercise. 2 Although physiological LVH does not confer increased morbidity and mortality, pathological LVH is consistently associated with prolongation of ventricular action potentials and alterations in the dispersion of repolarization, both of which result in electric instability and increase the propensity to develop lifethreatening arrhythmias. 3 Several lines of evidence suggest that these electric changes reflect, at least in part, alterations in the functioning of the K ϩ channels that underlie ventricular action potential repolarization. 3,4 Various experimental models of LVH, 5-7 including pressure overload-induced LVH, 8,9 have been developed to explore the mechanisms underlying K ϩ current remodeling.Although several studies have examined regional differences in remodeling, 8 -11 few have probed the underlying molecular and cellular mechanisms. In the studies here, a mouse model of pressure overload-induced LVH, produced by transverse aortic constriction (TAC), was exploited to quantify the effects of LVH on repolarizing K ϩ currents in LV myocytes and to delineate the mechanisms underlying K ϩ current remodeling. These experiments revealed that APDs were prolonged in TAC LV myocytes and that QT c intervals were increased in TAC mice. Mean whole-cell membrane capacitance (C m ) was increased significantly, and the densities of voltage-gated K ϩ (Kv) and inwardly rectifying K ϩ (Kir) currents were reduced in TAC LV myocytes. Further electrophysiological, molecular, and biochemical analyses revealed marked regional differences in the effects of LVH and that distinct cellular and molecular mechanisms contribute to the functional remodeling of repolarizing Kv and Kir currents.

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“…To address this issue, we are currently characterizing mice with deletion of CaMKII␥. In addition, in this work we used a pressure overload model involving a degree of aortic stenosis (27 g) that results in hypertrophy and pathological cardiac remodeling rather than heart failure (36). It remains to be determined whether CaMKII␦, in addition to its role in the control of fetal gene activation and hypertrophy, might also contribute to changes in EC coupling under heart failure conditions.…”

Section: Discussionmentioning

confidence: 99%

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Backs

Neef

et al. 2009

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

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391

360

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Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKII␦, the major CaMKII isoform expressed in the heart, we generated CaMKII␦-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKII␦-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKII␦-null mice, underscoring the specificity of the CaMKII␦ signaling pathway for HDAC4 phosphorylation. We conclude that CaMKII␦ functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKII␦ as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.histone deacetylase 4 (HDAC4) ͉ calcium signaling ͉ excitation contraction coupling (EC coupling) ͉ thoracic aortic constriction (TAC) ͉ CaM Kinase II inhibitory peptide (AC3-I)

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Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload

Abstract: In this experimental setting, calcineurin blockade with CsA prevented LV hypertrophy due to pressure overload. TAB mice treated with CsA maintain normal LV size and systolic function.

Cited by 283 publications

References 40 publications

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo

Left Ventricular Hypertrophy

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

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