IGF-1 induces iNOS expressionviathe p38 MAPK signal pathway in the anti-apoptotic process in pulmonary artery smooth muscle cells during PAH

Abstract

Apoptosis and cell proliferation are two important cellular processes that determine the accumulation of pulmonary artery smooth muscle cells (PASMC) during pulmonary arterial hypertension (PAH). Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, also tissue repair. Inducible nitric oxide synthase (iNOS) has been shown to serve many vasoprotective roles in vascular smooth muscle cells (VSMCs) including inhibition of VSMC proliferation and migration and stimulation of endothelial cell growth. In this study, we investigated the involvement of iNOS in the process of IGF-1-induced inhibition of PASMC apoptosis. We also examined the role of p38 mitogen-activated protein kinase (MAPK) in the IGF-1-induced iNOS activation. Our results show that exogenous IGF-1 induced the up-regulation of iNOS in PASMC. Immunofluorescence of IGF-1 and iNOS showed a decreased immunostaining of both IGF-1 and iNOS in the cytoplasm and the perinucleus under serum deprivation condition. iNOS inhibition in PASMC in vitro markedly induced IGF-1-mediated anti-apoptosis as assessed by the cell viability measurement, Western blot, mitochondrial potential analysis and nuclear morphology determination. A p38 MAPK inhibitor blocked all the effects of IGF-1 on iNOS. Our findings suggest that IGF-1 inhibits cells apoptosis in PASMC by activating the p38 MAPK-iNOS transduction pathway. This mechanism may contribute to the accumulation of PASMC in early human PAH.

Nogo-B Receptor Modulates Pulmonary Artery Smooth Muscle Cell Function in Developing Lungs

“…The three major pathways we investigated were MAPK, Akt/ protein kinase B, and ER stress. Decreased NgBR levels and increased ROS formation in HTFL PASMCs were associated with increased phosphorylation of ERK (25), which is known to promote the growth of smooth muscle cells. Previous studies have shown cross-talk between MAPK and ROS formation (40).…”

“…MAPKs (ERK and p38) and Akt regulate vascular smooth muscle cell growth (24,25,31). We examined whether they are also involved in the NgBR-regulated PASMC function.…”

“…Multiple mechanistic pathways can regulate ROS formation in PASMCs, including ER stress (18)(19)(20), nicotinamide adenine dinucleotide phosphate reduced oxidase (15), xanthine oxidase, mitochondrial oxidative phosphorylation, et cetera (21). ROS promote vascular smooth muscle cell growth and migration via phosphorylation of Akt (22) and extracellular signal-regulated kinase (ERK) (23)(24)(25). Oxidative stress to the ER can further increase ROS formation secondary to unfolded protein response (UPR) (3,20).…”

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

“…Data are presented as means (6SE). has been shown to inhibit apoptosis through an increase in p38, MAPK, and inducible nitric oxide synthase expression (20). In vivo, transgenic mice with an overexpression of IGF-1 in SMCs develop hyperplasia and increased SMC layer thickness in several organs without a change in plasma IGF-1 levels, implicating a paracrine effect (21).…”

Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction

“…By significantly lowering HCY, the administration of short-term rhGH would appear to have exerted a beneficial effect on any adverse effect that sustained elevated HCY might cause. The vascular protective role of IGF-I has been suggested because of its ability to stimulate NO production from endothelial and vascular smooth muscle cells [51]. IGF-I may also play a role in aging, atherosclerosis and cerebrovascular disease.…”