Abstract
Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.
Highlights
Diabetes mellitus (DM) is one of the most prevalent chronic diseases with significant morbidity and mortality
Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease
We evaluated the effect of BGP-15, an emerging anti-diabetic drug candidate, on osteochondrogenic transformation and mineralization of vascular smooth muscle cells (VSMCs)
Summary
Diabetes mellitus (DM) is one of the most prevalent chronic diseases with significant morbidity and mortality. Having stated by the Global Burden of Disease (GBD) report for 2015, the prevalence of DM increased from 330 million persons in 2005 to 435 million in 2015 [1] with a significant rise of annual deaths from DM [2]. Long-term complications of DM include diabetic retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Vascular calcification (VC) is a frequent complication of DM [3,4]. Intimal calcification is commonly associated with atherosclerosis, while medial calcification mainly develops in patients with DM [5] and chronic kidney disease [6]. Medial calcification is a significant independent predictor of cardiovascular mortality in diabetic patients [7]
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