Signaling Pathways Involved in Human Vascular Smooth Muscle Cell Proliferation and Matrix Metalloproteinase-2 Expression Induced by Leptin

Abstract

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-B (NF-B) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-B. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKCdependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-B pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes. Diabetes

Metformina minimiza as alterações morfométricas no músculo sóleo de ratos submetidos à imobilização articular

“…Esses fatores associados podem estar limitando a formação do colágeno e indiretamente protegendo a fibra muscular imobilizada (27,28) . Esse achado é extremamente importante, porém, são necessários mais estudos para determinar o mecanismo pelo qual a metformina minimizou o aumento da densidade de área do tecido conjuntivo no músculo imobilizado durante sete dias, já que tais alterações determinam a elasticidade, rigidez e extensibilidade muscular.…”

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

“…Leptin has been shown to enhance the proliferation of human aortic VSMCs and MMP-2 expression, with concomitant increased generation of intracellular ROS and activation of PKC, ERK1/2 and NF-κB. Metformin inhibited the ROS production and PKC, ERK1/2 and NF-κB activation (Li et al 2005). In addition, a different group showed that leptin induces hypertrophy in rat VSMCs via the p38MAPK pathway (Shin et al 2005).…”

The levels of the leptin and adiponectin according to body mass index and their relationship with oxidative parameters

“…Leptin reseptörleri yapı ve fonksiyon açısından interlökin-6 gibi sitokin reseptörlerine benzemekte ve inflamasyonda rol oynamaktadırlar (28). Endoteliyal hücrelerin leptin ile uyarılması hücre içinde H 2 O 2 ve HO gibi reaktif oksijen türlerinin aşırı birikimine ve metalloproteinaz-1 ekspresyonunda artışa neden olmaktadır (29). Bu artışta leptin aracılı tirozin kinaz reseptörleri de rol oynamaktadır (30).…”