transforming-growth-factor-beta and Acute-Coronary-Syndrome

Transforming growth factor-β-induced protein (TGFBIp) is released from activated platelets and promotes pro-thrombotic complications like pulmonary embolism. The role of TGFBIp in acute coronary syndrome, especially with a focus on platelets, has not been investigated so far. Using ELISA and immunoblotting, we demonstrate platelet TGFBIp release in patients with myocardial infarction (MI). We investigated TGFBIp-induced platelet adhesion and rolling by flow chamber and chemotactic effects of TGFBIp in transwell experiments. Immunochemistry staining of arterial vessels detected TGFBIp and the platelet-specific protein GPVI in the vessel wall.We demonstrate for the first time that platelet TGFBIp release is significantly increased in MI and correlates with the severity of acute coronary syndromes (STEMI, NSTEMI). After activation with TRAP, platelets release TGFBIp and TGFBIp itself activates platelets. Under flow, TGFBIp-mediated platelet rolling and adherence similarly to collagen. TGFBIp significantly increased platelet transmigration and we demonstrate TGFBIp deposits in the wall of human arteries. In this study, we add novel aspects to the role of TGFBIp in acute coronary syndrome by demonstrating that TGFBIp is partially released from platelets during MI and has activating, pro-adhesive and pro-migratory effects on platelets that could contribute to the disease development of coronary vascular inflammation and MI.

Topics: Acute Coronary Syndrome; Blood Platelets; Collagen; Extracellular Matrix Proteins; Humans; Myocardial Infarction; Transforming Growth Factor beta; Transforming Growth Factors

Recent studies have shown that circulating microRNAs (miRNA) play a critical role in diagnosing acute coronary syndrome (ACS). This study aims to investigate the effect of miR-224 on atherosclerotic plaques forming and vascular remodeling in ACS and its relationship with TGF-β/Smad pathway. Myocardial infarction (MI) rat model was established and lentivirus vector of miR-224 inhibitor was prepared for investigating the effect of downregulated miR-224 on the contents of nitric oxide (NO) and endothelin-1 (ET-1), blood lipid levels and inflammatory factor levels in serum as well as the TGF-β/Smad pathway. The rats suffering from MI had decreased survival rates and exhibited reduced levels of NO, high-density lipoprotein cholesterol, and lumen diameter, and Smad7 messenger RNA (mRNA) and protein expression; while had significantly increased ratio of heart weight or body weight, levels of ET-1, inflammatory factors, blood lipid indexes, vascular remodeling indexes, collagen volume fraction, vulnerable atherosclerotic plaque area, VCAM-1 and MMP-2 protein expression, TGF-β, Smad2, Smad3, and Smad4 mRNA and protein expression. After inhibiting the TGF-β/Smad pathway, the rats suffering from MI showed notably opposite trend. In conclusion, downregulation of miR-224 expression promotes the formation of vulnerable atherosclerotic plaques and vascular remodeling in ACS through activation of the TGF-β/Smad pathway. Therefore, this study provides a new therapeutic target for ACS.

Topics: Acute Coronary Syndrome; Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Matrix Metalloproteinase 2; MicroRNAs; Myocardial Infarction; Plaque, Atherosclerotic; Rats; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1; Vascular Remodeling

Acute coronary syndrome (ACS) is the leading cause of death in elderly patients worldwide. Due its participation in apoptosis, fibrosis, and angiogenesis, transforming growth factor-β (TGF-β) isoforms had been categorized as risk factors for cardiovascular diseases. However, due their contradictory activities, a cardioprotective role has been suggested. The aim was to measure the plasma levels of TGF-β1, 2, and 3 proteins in patients with ACS. This was a case-control study including 225 subjects. The three activated isoforms were measured in serum using the Bio-Plex Pro TGF-β assay by means of magnetic beads; the fluorescence intensity of reporter signal was read in a Bio-Plex Magpix instrument. We observed a significant reduction of the three activated isoforms of TGF-β in patients with ACS. The three TGF-β isoforms were positively correlated with each other in moderate-to-strong manner. TGFβ-2 was inversely correlated with glucose and low-density lipoprotein (LDL)-cholesterol, whereas TGF-β3 was inversely correlated with the serum cholesterol concentration. The production of TGF-β1, TGF-β2, and TGF-β3 are decreased in the serum of patients with ACS. Further follow-up controlled studies with a larger sample size are needed, in order to test whether TGF-β isoforms could be useful as biomarkers that complement the diagnosis of ACS.

Topics: Acute Coronary Syndrome; Adult; Aged; Biomarkers; Case-Control Studies; Cholesterol; Cholesterol, LDL; Female; Humans; Male; Middle Aged; Protein Isoforms; Transforming Growth Factor beta

Regulatory T (Treg) cells play a protective role in atherosclerosis prone models and are related to the onset of acute coronary syndromes (ACS, including non-ST-elevation ACS (NSTEACS) and ST-elevation acute myocardial infarction (STEAMI)). CD4+LAP+ Treg cells are a novel subset of Tregs that have been found to ameliorate atherosclerosis in ApoE(-/-) mice, and these cells also exist in humans. The present study was designed to investigate whether CD4+LAP+ Treg cells are involved in the onset of ACS.. The frequencies of CD4+LAP+ and CD4+CD25+ Treg cells were detected using flow cytometric analysis, and the plasma IL-10 and TGF- β 1 levels were measured using an ELISA in 29 stable angina (SA) patients, 30 NSTEACS patients, 27 STEAMI patients, and a control group (30 cases).. The results revealed a significant decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells and in the levels of IL-10 and TGF- β 1 in patients with ACS compared with those in the SA and control groups.. The decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells may play a role in the onset of ACS.

Topics: Acute Coronary Syndrome; Aged; Down-Regulation; Female; Forkhead Transcription Factors; Humans; Interleukin-10; Male; Middle Aged; Peptides; Protein Precursors; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Function, Left

CD4⁺CD25⁺ regulatory T cells (Tregs) mediate immune suppression and prevent autoimmune disorders. Recently, Tregs were found to present in atherosclerotic lesions and play an important role in the progression of atherosclerosis. Statins have immunomodulatory properties, and the effect of statins on atherosclerosis depends in part on their immunomodulatory mechanisms. We sought to determine whether statins exhibit an effect on Tregs in atherosclerotic plaques and in peripheral circulation of patients with acute coronary syndrome (ACS). In an in vivo experiment, we induced atherosclerotic plaques in apolipoprotein E-deficient (ApoE⁻/⁻) mice. The mice were randomly divided into two groups for 6-wk treatment: simvastatin (50 mg/kg/d) or vehicle (control). Simvastatin significantly increased the number of Tregs and the expression of Treg marker Foxp3 (Forkhead/winged helix transcription factor), transforming growth factor (TGF)-β and interleukin (IL)-10 in atherosclerotic plaques. Moreover, simvastatin played an important role in modulating the balance between antiinflammatory (Tregs and Th2 cells) and proinflammatory (Th17 and Th1 cells) subsets of T cells. In an in vitro experiment, peripheral blood mononuclear cells (PBMCs) were isolated from patients with ACS and incubated with simvastatin. After an incubation for 96 h, simvastatin significantly enhanced the frequency and functional suppressive properties of Tregs. Therefore, statin treatment may influence Tregs in atherosclerotic lesions. Furthermore, statins improved the quantity and suppressive function of Tregs in ACS patients.

Topics: Acute Coronary Syndrome; Animals; Body Weight; Cytokines; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-10; Leukocytes, Mononuclear; Lipid Metabolism; Male; Mice; Mice, Knockout; Plaque, Atherosclerotic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Th17 cells producing IL-17 are involved in the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. In this study, we investigated the effects of IL-17 on human vascular endothelial cells and showed that IL-17 induced cell death of the vascular endothelial cells, which played a pivotal role in plaque destabilization triggering acute coronary syndrome (ACS). We showed that circulating Th17 cells and IL-17 increased in patients with ACS compared to the patients with stable angina or health individuals; the plasma levels of IL-6 increased but TGF-β decreased in ACS patients, exhibiting a positive and negative correlation with that of IL-17, respectively. Importantly, we uncovered that IL-17 promoted the production of von Willebrand factor by endothelial cells and induced endothelial apoptosis by activating caspase-3, caspase-9 and up-regulating the ratio of Bax/Bcl-2, indicating the function of IL-17 in vascular endothelial damage as a potential mechanism for the pathogenesis of human ACS.

Topics: Acute Coronary Syndrome; Angina, Stable; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cells, Cultured; Coronary Artery Disease; Endothelial Cells; Female; Gene Expression Regulation; Humans; Interleukin-17; Interleukin-6; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Recombinant Proteins; Th17 Cells; Transforming Growth Factor beta; Up-Regulation; von Willebrand Factor