Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice

Abstract

ABBREVIATIONS: AMPK, AMP-activated protein kinase; ANP, atrial natriuretic peptide; GPx1, glutathione peroxidase 1; IL-6, interleukin-6; MMP-2, matrix metallopeptidase 2; MMP-9, matrix metallopeptidase 9; TGF-β, transforming growth factor-β. The present study examined whether metformin treatment prevents isoporterenol-induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-β, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP-2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-β, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress.

Cardiac fibroblast‐specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin‐6 signaling mechanism

“…A marked elevation of cardiac Il6 mRNA levels has previously been reported LV samples from ISO-infused mice after 1–2 wk (42, 43). We observed a trend toward increased Il6 mRNA levels in hearts from ISO-treated control mice after 3 wk, which was not apparent in hearts from ISO-treated fibroblast-specific p38 KO mice.…”

“…A number of paracrine-signaling molecules have been identified through which fibroblasts can modulate cardiomyocyte hypertrophy, including FGF2, IGF-1, and TGF-β. Additionally, we hypothesized that IL-6 may act in this manner because that cytokine is up-regulated in mouse hearts after 1–2 wk of ISO infusion (42, 43), is actively secreted from cardiac fibroblasts in response to β-adrenergic receptor stimulation or Ang II (19), and is able to directly induce cardiomyocyte hypertrophy (44, 45), and IL-6 KO mice are protected against LV hypertrophy in response to noradrenaline, Ang II, or pressure overload (44, 46, 47). Moreover, cardiomyocyte hypertrophy induced in vitro by either Ang II or phenylephrine is impaired in myocytes isolated from IL-6 KO mice (44), suggesting that autocrine IL-6 secretion is necessary for induction of myocyte hypertrophy by those stimuli.…”

Short-term treatment with metformin suppresses toll like receptors (TLRs) activity in isoproterenol-induced myocardial infarction in rat: Are AMPK and TLRs connected?

“…It has been reported that the cardioprotective of AMPK activation during myocardial ischemia and reperfusion disappeared in transgenic mice with AMPK deficiency [31]. In contrast, some studies reported that the cardioprotective effects of metformin can be AMPK independent [32,33]. AMPK is a heterotrimeric kinase, which is formed of α, β, and γ subunits.…”

Perivascular fat, AMP‐activated protein kinase and vascular diseases

“…In the vasculature, metformin‐induced AMPK activation has been reported to up‐regulate eNOS phosphorylation, increase NO bioavailability (Calvert et al ., ; Zhang et al ., ) and reduce SMC proliferation, migration and inflammatory responses (Kim and Choi, ; Vigetti et al ., ). In cardiac tissue, metformin‐induced AMPK activity sustains energy balance, cardiomyocyte function and myocardial viability (Cha et al ., ; Fu et al ., ). The reported cardioprotective effect is principally achieved by the reduction of hypertrophic cell growth and endoplasmic reticulum (ER) stress (Dong et al ., 2010a).…”