Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Abstract

Vascular calcification, which results from a process osteoblastic differentiation of vascular smooth muscle cells (VSMCs), is a major risk factor for cardiovascular morbidity and mortality. Apelin is a recently discovered peptide that is the endogenous ligand for the orphan G-protein-coupled receptor, APJ. Several studies have identified the protective effects of apelin on the cardiovascular system. However, the effects and mechanisms of apelin on the osteoblastic differentiation of VSMCs have not been elucidated. Using a culture of calcifying vascular smooth muscle cells (CVMSCs) as a model for the study of vascular calcification, the relationship between apelin and the osteoblastic differentiation of VSMCs and the signal pathway involved were investigated. Alkaline phosphatase (ALP) activity and osteocalcin secretion were examined in CVSMCs. The involved signal pathway was studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, and APJ siRNA. The results showed that apelin inhibited ALP activity, osteocalcin secretion, and the formation of mineralized nodules. APJ protein was detected in CVSMCs, and apelin activated ERK and AKT (a downstream effector of PI3-K). Suppression of APJ with siRNA abolished the apelin-induced activation of ERK and Akt. Furthermore, inhibition of APJ expression, and the activation of ERK or PI3-K, reversed the effects of apelin on ALP activity. These results showed that apelin inhibited the osteoblastic differentiation of CVSMCs through the APJ/ERK and APJ/PI3-K/AKT signaling pathway. Apelin appears to play a protective role against arterial calcification.

Overexpression of C1q/Tumor Necrosis Factor–Related Protein-3 Promotes Phosphate-Induced Vascular Smooth Muscle Cell Calcification Both In Vivo and In Vitro

“…6 Omentin and apelin inhibit ALP activity and osteocalcin production during the osteoblastic differentiation of calcifying VSMCs. 7,8 In the present study, we found that expressions of SMA and smooth muscle 22α were significantly decreased in the abdominal aortas of CRF rats, and overexpression of CTRP3 further reduced the expression of contractile markers. In contrast, increased osteogenic markers in CRF rats were further upregulated in CTRP3-overexpressed vasculature.…”

“…27 More importantly, Runx2 is closely associated with the effects of various adipokines in osteogenic transition of VSMCs. Adiponectin and apelin decrease Runx2 expression in cultured calcifying VSMCs, 6,8 whereas tumor necrosis factor-α enhances the mRNA expression and DNA binding of Runx2. 29,30 Here, we found that the expression of Runx2 increased significantly in the abdominal aortas of CRF rats.…”

“…Adiponectin exerts its anticalcific effect through p38MAPK, 6 whereas apelin plays a protective role against vascular calcification via ERK1/2 pathway. 8 CTRP3 is reported to promote mouse VSMC proliferation via ERK1/2 and p38MAPK, 12 and it also promotes the proliferation and migration of murine osteosarcoma cells and endothelial cells by activating ERK1/2.…”

“…4,5 In contrast, several adipokines, including adiponectin, omentin, and apelin, can play a protective role against vascular calcification by inhibiting osteoblastic differentiation of vascular smooth muscle cells (VSMCs). [6][7][8] However, the precise roles of adipokines in vascular calcification regulation and the underlying mechanisms still require further investigation.…”

RANKL is a downstream mediator for insulin-induced osteoblastic differentiation of vascular smooth muscle cells

“…However, the relationship between insulin and VSMCs calcification remains controversial [17,18]. In the present study, we used calcifying vascular smooth muscle cells (CVSMCs), referred to as a specific subpopulation of VSMCs that could express osteoblastic phenotype gene and form calcification nodule spontaneously [19,20], to elucidate the effect of insulin on osteoblastic differentiation of CVSMCs and the mechanisms involved.…”