Adipocyte-Derived Plasma Protein Adiponectin Acts as a Platelet-Derived Growth Factor-BB–Binding Protein and Regulates Growth Factor–Induced Common Postreceptor Signal in Vascular Smooth Muscle Cell

Abstract

Background — Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs). Methods and Results — HASMC proliferation was estimated by [ 3 H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to 125 I-PDGF-BB and significantly inhibited the association of 125 I-PDGF-BB with HASMCs, but no effects were observed on the binding of 125 I-PDGF-AA or 125 I-heparin–binding epidermal growth factor (EGF)–like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB–induced p42/44 extracellular signal–related kinase (ERK) phosphorylation and PDGF β-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA–stimulated or HB-EGF–stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF α-receptor or EGF receptor. Conclusions — The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor–stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

“…It has been demonstrated that adiponectin inhibits the expression of adhesion molecules in endothelial cells and inhibits smooth muscle cell proliferation. It also inhibits the differentiation of monocytes into macrophages and the formation of foam cells and secretion of TNF-α by macrophages [55][56][57]. Increased adiponectin levels are related to improvement in the differentiation of preadipocytes into adipocytes, a process that is usually impaired in obese subjects [58].…”

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

“…APN-deficient mice have increased thrombus volume after laser-induced carotid arterial injury; restoration of a normal APN level with an adenovirus expressing APN rescues the thrombotic phenotype [21] . APN may suppress atherosclerosis via reduction of collagen-induced platelet aggregation [21] , suppression of expression of vascular adhesion molecules scavenger receptors [22] , suppression of the proliferation of smooth muscle cells (SMCs) and their directed migration to platelet-derived growth factor-BB, inhibition of growth factorstimulated ERK signaling in human aortic SMCs [23] , inhibition tumor necrosis factor (TNF) level and resultant inflammatory TNF effects on endothelial function through a cAMP-PKA dependent pathway [24] . Recent accumulating evidence has demonstrated APN's anti-inflammatory actions are related to 5'-AMP-activated protein kinase (AMPK)-induced activation of endothelial nitric oxide (eNOS), with subsequent release of bioavailable NO from endothelium cells [25] .…”

The ‘beneficial’ adipokines in reproduction and fertility

“…10 In human aortic endothelial cells, the cyclic AMP or protein kinase A pathway was evoked by adiponectin, 68,69 whereas in other endothelial cell models, the phosphoinositol kinase 3/protein kinase B (PKB) or Akt system transduces the adiponectin signal. 34 There is evidence for adiponectin activation of the peripheral peroxisome-activated receptor-g in placental tissue 57 and mitogen-activated protein kinase pathways in vascular tissue 70,71 and osteoblasts. 72 The recent discovery of interactions between the AdipoR1 and R2 and the adapter protein APPL1 28,29 has provided new insight into the mechanism by which adiponectin can act on target tissues.…”