BGP-15 Inhibits Hyperglycemia-Aggravated VSMC Calcification Induced by High Phosphate.
Annamária NagyDávid PethőRudolf GesztelyiBéla JuhászGyörgy BallaZoltán SzilvássyJózsef BallaTamás GállPublished in: International journal of molecular sciences (2021)
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.
Keyphrases
- fluorescent probe
- high glucose
- chronic kidney disease
- endothelial cells
- vascular smooth muscle cells
- diabetic rats
- gene expression
- end stage renal disease
- extracellular matrix
- smooth muscle
- type diabetes
- drug induced
- angiotensin ii
- mesenchymal stem cells
- wound healing
- poor prognosis
- emergency department
- single cell
- skeletal muscle
- metabolic syndrome
- cell therapy
- long non coding rna
- tyrosine kinase
- adipose tissue
- bone marrow
- stress induced