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Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function
Author(s) -
Nam Deok Hwa,
Kim Eunah,
Benham Ashley,
Park Hye-Kyung,
Soibam Benjamin,
Taffet George E.,
Kaelber Jason T.,
Suh Ji Ho,
Taegtmeyer Heinrich,
Entman Mark L.,
Reineke Erin L.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800602r
Subject(s) - ampk , pressure overload , endocrinology , medicine , ventricular remodeling , cardiac function curve , signal transduction , cardiac fibrosis , phosphorylation , chemistry , fibrosis , biology , heart failure , microbiology and biotechnology , muscle hypertrophy , protein kinase a , cardiac hypertrophy
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. FASEB J. 33, 711–721 (2019). www.fasebj.org