Transforming Growth Factor β1 (TGF-β1) Appears to Promote Coronary Artery Disease by Upregulating Sphingosine Kinase 1 (SPHK1) and Further Upregulating Its Downstream TIMP-1

Abstract

BackgroundTransforming growth factor (TGF)-β1 is involved in the pathogenesis of coronary artery disease (CAD), but the mechanism of its action remains unclear. Our study aimed to investigate the role of TGF-β1 in CAD and to explore the possible mechanisms.Material/MethodsA total of 60 CAD patients and 54 healthy people were included in this study. Blood samples were drawn from each participant to prepare serum. ELISA was utilized to measure serum level of TGF-β1. TGF-β1 expression vector, TGF-β1 siRNA, and TIMP-1 siRNA were transfected into human primary coronary artery endothelial cell (HCAEC) line cells, and expression of TGF-β1 sphingosine kinase 1 (SPHK1) and TIMP metallopeptidase inhibitor 1 (TIMP-1) was detected by Western blot. Cell apoptosis was detected by MTT assay.ResultsSerum level of TGF-β1 was specifically higher in patients with CAD than in healthy controls. Serum levels of active TGF-β1 can be used to effectively distinguish CAD patients from healthy controls. TGF-β1 overexpression promoted the apoptosis of HCAEC and TGF-β1 siRNA silencing inhibited the apoptosis of HCAEC. TGF-β1 overexpression also promoted the expression of SPHK1 and TIMP-1. SPHK1 overexpression upregulated TIMP-1 but it showed no significant effects on TGF-β1. TIMP-1 overexpression showed no significant effects on TGF-β1 or SPHK1. SPHK1 inhibitor and TIMP-1 silencing reduced the enhancing effects of TGF-β1 overexpression on cell apoptosis.ConclusionsTGF-β1 appears to promote CAD through the induction of cell apoptosis by upregulating SPHK1 expression and further upregulating its downstream TIMP-1.

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

“…The involvement of SPHK1 [50] and WWTR1 [51] with renal diseases was demonstrated previously. Several studies have shown that altered expression of SPHK1 [52], ADTRP (androgen dependent TFPI regulating protein) [53] and DNMT3A [54] can be a strong prognosis biomarkers to predict relapse in patients with cardiovascular complications.…”

Transcriptional Regulation of Sphingosine Kinase 1

“…Transforming growth factor-B (TGF-B) signaling is known to upregulate and activate SK1, and SK1 activity has been shown to be important in many TGF-B dependent pathways. Treatment of fibroblasts with TGF-B led to increased SK1 expression, which was required for TIMP-1 upregulation [57,58]. TGF-B induced upregulation of SK1 has been shown to be important in coronary artery disease and liver fibrosis [58,59].…”

“…Treatment of fibroblasts with TGF-B led to increased SK1 expression, which was required for TIMP-1 upregulation [57,58]. TGF-B induced upregulation of SK1 has been shown to be important in coronary artery disease and liver fibrosis [58,59]. In breast cancer, TGF-B driven SK1 upregulation has been implicated in bone metastasis [60].…”

Do exosomes play role in cardiovascular disease development in hematological malignancy?

“…Studies have shown that TGF-β1 secretion unlike MDSC does not induce cardiomyocyte repairing; it increases the expression of both sphingosine kinase 1 (SPHK1) and TIMP metallopeptidase inhibitor 1 (TIMP-1). These two factors cause angiogenesis and regulate metabolism, normally, but increasing expression by TGF-β1 leads to cardiomyocyte apoptosis and CVD [56]. It has been proven that, TGF-β1 leads to increased expression of neural adhesion molecule 1 (NCAM1) in CVD patients; NCAM1 expression leads to impaired cardiomyocyte adhesion and impaired cardiac function, consequently (Fig.…”