Adropin Inhibits Vascular Smooth Muscle Cell Osteogenic Differentiation to Alleviate Vascular Calcification via the JAK2/STAT3 Signaling Pathway

Abstract

Vascular calcification is characterized as the deposition of hydroxyapatite mineral in the form of calcium-phosphate complexes in the vasculature. Transdifferentiation between vascular smooth muscle cells (VSMCs) and osteoblast-like cells is considered essential in the progression of vascular calcification. The pathophysiological mechanisms underlying vascular calcification and VSMC osteogenic differentiation remain to be fully elucidated, and the development of novel therapies is required. In the present study, PCR and western blot analysis were conducted to quantify the mRNA and protein expression levels of calcification-associated markers (bone morphogenetic protein 2, alkaline phosphatase, osteoprotegerin, osteocalcin, and runt-related transcription factor 2) and adropin in VSMCs and rat vascular tissues. The calcification of VSMCs was assessed using alizarin red staining. Moreover, adropin expression levels in VSMCs were analyzed using immunofluorescence. Lentiviral transfection and small interfering RNA were used for overexpression and knockdown of adropin in VSMCs, respectively. The results demonstrated that adropin alleviated vascular calcification in vivo. Moreover, adropin also inhibited osteogenic differentiation and the calcification of VSMCs in vitro. Notably, results of the present study revealed that the tyrosine protein kinase JAK2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway played a key role in the aforementioned inhibition. In conclusion, the results of the present study demonstrated that adropin inhibited VSMC osteogenic differentiation to alleviate vascular calcification via the JAK2/STAT3 signaling pathway.

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes

“…In addition to the role played in endothelial health, adropin has been reported to have direct effects on VSMCs. In VSMCs, adropin attenuated angiotensin II-induced cell migration and proliferation via regulation of the adenosine monophosphate-activated protein kinase/acetyl-CoA carboxylase signaling pathway (36,183). Furthermore, adropin suppressed angiotensin IIinduced phenotypic modulation of VSMCs.…”

“…When reassessed in mice lacking eNOS, there was no increase in leg blood flow following adropin administration (8), suggesting that adropin-mediated increases in capillarization and leg blood flow are eNOS dependent. In addition, adropin protects against vascular calcification in rats (183). The calcification of the vasculature is associated with the transdifferentiation of VSMCs into osteoblastlike cells and an increased risk of atherosclerotic plaque ruptures (180).…”

“…The calcification of the vasculature is associated with the transdifferentiation of VSMCs into osteoblastlike cells and an increased risk of atherosclerotic plaque ruptures (180). Adropin inhibited the osteogenic transdifferentiation in VSMC (183). In ApoE knockout mice, a model of atherosclerosis, adropin decreased atherosclerotic lesion size, reduced aortic monocyte/macrophage infiltration, and decreased VSMC proliferation (36).…”

Adropin Predicts Chronic Kidney Disease in Type 2 Diabetes Mellitus Patients with Chronic Heart Failure

“…Yet, adropin ameliorates the flexibility of metabolic homeostasis through increasing glycolytic flux via both oxidative and non-oxidative pathways and downregulating skeletal muscle fatty acid uptake by an expression of the sarcolemmal fatty acid translocase [ 51 , 53 , 54 ]. Finally, adropin improves insulin sensitivity, suppresses oxidative stress and mitochondrial dysfunction, and attenuates the worsening repair potency of precursors via the activation of Akt phosphorylation, transcription 3 (STAT3) signalling, the glucose transporter 4 receptor, and tyrosine protein kinase JAK2 (JAK2)/signal transducer pathways [ 55 , 56 ]. In addition to that, adropin was able to directly promote microangiogenesis, increase microvessel density, suppress oxidative stress, and inhibit myocardial fibrosis and apoptosis regardless of its capability of ameliorating glucose and lipid metabolism [ 57 ].…”

Emerging Evidence Linking the Liver to the Cardiovascular System: Liver-derived Secretory Factors

“… 54 Although short-term administration of adropin may fail to exert a protective effect on cardiac function in obese animals. 55 Besides, adropin could promote eNOS activation and perfusion recovery after hindlimb ischemia by upregulating VEGFR2, 56 suppress proliferation and phenotypic modulation of VSMCs induced by angiotensin II via AMPK/ACC signaling, 46 and attenuate vascular calcification by repressing VSMCs osteogenic differentiation through JAK2/STAT3 signaling, 57 as well as inhibit TNF-α-induced THP1 monocyte adhesion to VECs, prevent macrophages from polarizing into a pro-inflammatory phenotype and reduce the formation of atherosclerotic lesions in apoE −/− mice. 58 Additionally, exposure to cell-free hemoglobin resulted in decreased expressions of adropin and increased paracellular permeability of VECs, and treatment with adropin was able to protect against the hyperpermeability and suppress macrophage trans-endothelial migration.…”