{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:12:16Z","timestamp":1790233936021,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,1,20]],"date-time":"2014-01-20T00:00:00Z","timestamp":1390176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\u2010kinase (<jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti\u2010hypertrophic action of metformin, specifically, the role of the <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24\u00a0hrs in the presence or absence of metformin (<jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> agonist), losartan [AngII type 1 receptor (AT1R) blocker], N\u03c9\u2010nitro\u2010L\u2010arginine methyl ester (L\u2010<jats:styled-content style=\"fixed-case\">NAME<\/jats:styled-content>, pan\u2010<jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content> inhibitor), splitomicin (<jats:styled-content style=\"fixed-case\">SIRT<\/jats:styled-content>1 inhibitor) or pifithrin\u2010\u03b1 (p53 inhibitor). Results showed that treatment with metformin significantly attenuated AngII\u2010induced cell hypertrophy and death. Metformin attenuated AngII\u2010induced activation (cleavage) of caspase 3, Bcl\u20102 down\u2010regulation and p53 up\u2010regulation. It also reduced AngII\u2010induced AT1R up\u2010regulation by 30% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and enhanced <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> phosphorylation by 99% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and P\u2010e<jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content> levels by 3.3\u2010fold (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Likewise, losartan reduced AT1R up\u2010regulation and enhanced <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> phosphorylation by 54% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). The <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> inhibitor, compound C, prevented AT1R down\u2010regulation, indicating that metformin mediated its effects <jats:italic>via <\/jats:italic><jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> activation. Beneficial effects of metformin and losartan converged on mitochondria that demonstrated high membrane potential (\u0394\u03c8<jats:sub>m<\/jats:sub>) and low permeability transition pore opening. Thus, this study demonstrates that the anti\u2010hypertrophic effects of metformin are associated with <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\u2010induced AT1R down\u2010regulation and prevention of mitochondrial dysfunction through the <jats:styled-content style=\"fixed-case\">SIRT<\/jats:styled-content>1\/e<jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content>\/p53 pathway.<\/jats:p>","DOI":"10.1111\/jcmm.12220","type":"journal-article","created":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T03:04:59Z","timestamp":1390273499000},"page":"709-720","source":"Crossref","is-referenced-by-count":86,"title":["Crosstalk between <scp>AMPK<\/scp> activation and angiotensin <scp>II<\/scp>\u2010induced hypertrophy in cardiomyocytes: the role of mitochondria"],"prefix":"10.1111","volume":"18","author":[{"given":"Jessica Soto","family":"Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Physiology School of Medicine 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