1. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function
- Author
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Ji Ho Suh, Eunah Kim, Erin L. Reineke, Mark L. Entman, Benjamin Soibam, George E. Taffet, Jason T. Kaelber, Ashley Benham, Deok Hwa Nam, Heinrich Taegtmeyer, and Hye Kyung Park
- Subjects
Male ,0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Cardiomegaly ,AMP-Activated Protein Kinases ,Biochemistry ,Ventricular Function, Left ,Muscle hypertrophy ,Mice ,Nuclear Receptor Coactivator 2 ,Ventricular Dysfunction, Left ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ventricular Pressure ,Genetics ,medicine ,Animals ,Hypoglycemic Agents ,Myocytes, Cardiac ,Molecular Biology ,Protein kinase B ,Mice, Knockout ,Pressure overload ,Ventricular Remodeling ,Chemistry ,Research ,AMPK ,Ribonucleotides ,Aminoimidazole Carboxamide ,medicine.disease ,030104 developmental biology ,Endocrinology ,Heart failure ,Ventricular pressure ,Signal transduction ,030217 neurology & neurosurgery ,Biotechnology - 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.
- Published
- 2018
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