Activation of AMP-Activated Protein Kinase Enhances Angiotensin II–Induced Proliferation in Cardiac Fibroblasts

Abstract

Abstract-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-␤-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. Key Words: cardiac function Ⅲ angiotensin Ⅲ hypertrophy Ⅲ signal transduction A MP-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. 1 AMPK is activated by conditions that increase the AMP:ATP ratio, such as exercise and metabolic stress. AMPK has been most extensively examined under conditions of stress, such as exercise and hypoxia-ischemia. When the AMP:ATP ratio increases, AMPK is activated by AMPK kinase to combine with AMP, thus inducing a conformational change and decreasing the AMP:ATP ratio by switching off ATP-consuming pathways and switching on ATP-generating pathways. 1 Considerable information exists regarding the regulation of AMPK activation in a variety of cell types, including cardiac cells. 2,3 There is a correlation between AMPK activation and the development of cardiac hypertrophy. 4,5 Pressure overload-induced hypertrophic cardiomyopathy is associated with increased AMPK activity. 4 In addition, AMPK plays a role in familial Wolff-Parkinson-White syndrome and hypertrophic cardiomyopathy via mutations in PRKAG2, a gene encoding the ␥2 subunit of AMPK. 6 -8 On the other hand, recent evidence indicates that AMPK activation inhibits proteins synthesis 9,10 and might, thus, be expected to reduce the development of hypertrophy. Although much has been learned about the role of AMPK in the development of cardiac hypertrophy, the molecular mechanism by which AMPK regulates cardiac hypertrophy is still unclear.Interstitial fibroblast proliferation and collagen accumulation is associated with compensatory remodeling of the hypertrophic myocardium, 11,12 and structural remodeling leads to diastolic and systolic dysfunction. 13 Angiotensin (Ang) II is closely involved in cardiac remodeling by stimulating hyperplastic growth of cardiac fibroblasts 14 and the synthesis of extracellular matrix proteins. 12 Therefore, we investigated the role of AMPK in cardiac remodeling using cardiac fibroblasts. We used 5-aminoimidazole-4-carboxamide-1-␤-ribofuranoside (AICAR), which is an adenosine analog, as well as cell-permeable activator of AMPK and a small interfering RNA (siRNA) for AMPK, which is an AMPK inhibitor. We examined the effects of both the AMPK activator and inhibitor on the extracellular sign...

Inhibition of smooth muscle cell proliferation by adiponectin requires proteolytic conversion to its globular form

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Activation of Peroxisome Proliferator–Activated Receptor β/δ Induces Lung Cancer Growth via Peroxisome Proliferator–Activated Receptor Coactivator γ-1α

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Hydrogen peroxide-mediated oxidative stress and collagen synthesis in cardiac fibroblasts: Blockade by tanshinone IIA

“…The effects of H 2 O 2 on DNA and collagen synthesis in cardiac fibroblasts were evaluated by the incorporation of [ 3 H]-thymidine and [ 3 H]-proline into cells, respectively, as described previously (Hattori et al, 2006). To examine DNA synthesis, 0.5 mCi of [ 3 H]-thymidine was added 12 h after treatment with H 2 O 2 , and the cells were incubated for 12 h. To examine collagen synthesis, 0.5 mCi of [ 3 H]-proline was added 12 h after treatment with H 2 O 2 , and the cells were incubated for 24 h. After labeling, the cells were rinsed twice with cold PBS and incubated with 10% trichloroacetic acid at 4 1C for 30 min.…”