Activation of AMP-activated protein kinase enhances angiotensin II-induced proliferation in cardiac fibroblasts

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. Here, we investigated whether AMPK signaling has a role in the regulation of angiotensin II (Ang II) -induced proliferation in rat cardiac fibroblasts. Aminoimidazole-4-carboxamide-1-beta-ribofuranoside ( AICAR) activated AMPK in rat cardiac fibroblasts and increased Ang II - induced extracellular signal - regulated kinase 1/2 phosphorylation and activity. AICAR also increased Ang II - induced c-fos mRNA expression in the cells. [H-3]-thymidine and [H-3]-proline incorporation by cardiac fibroblasts treated with Ang II was enhanced when the cells were pretreated with AICAR. Inhibition of AMPK by small interfering RNA for AMPK alpha 1 suppressed Ang II - induced extracellular signal - regulated kinase activity, c-fos mRNA expression, and cell proliferation. Treatment of rats with AICAR ( 1 mg/g body weight per day) for 1 week significantly enhanced Ang II - induced hypertrophy of the myocardium. Our findings indicate that AMPK works as a stimulator of the Ang II - induced proliferative pathway in cardiac fibroblasts. Inhibition of AMPK signaling might serve as a new therapeutic target of remodeling of the hypertrophic myocardium.