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Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

ABSTRACT: Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD⁺ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

SUBMITTER: Nam DH

PROVIDER: S-EPMC6355077 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

Nam Deok Hwa DH Kim Eunah E Benham Ashley A Park Hye-Kyung HK Soibam Benjamin B Taffet George E GE Kaelber Jason T JT Suh Ji Ho JH Taegtmeyer Heinrich H Entman Mark L ML Reineke Erin L EL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180719 1

Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. W ...[more]

PMID: 30024790

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Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

Publications

Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.

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