Role of matrix Gla protein in angiotensin II-induced exacerbation of vascular calcification.
Vascular calcification predicts an increased risk for cardiovascular events in atherosclerosis, diabetes, and end-stage kidney diseases. Matrix Gla protein (MGP), an inhibitor of calcification, limits calcium phosphate deposition in the vessel wall. There are many factors contributing to the progression of atherosclerosis, including hypertension, hyperlipidemia, the renin-angiotensin system, and inflammation. Angiotensin II (ANG II) plays a crucial role in the atherogenic process through not only its pressor responses but also its growth-promoting and inflammatory effects. In this study, we investigated the role of MGP in ANG II-induced exacerbation of vascular calcification in human vascular smooth muscle cells (VSMCs). The expression of MGP, calcification, and apoptosis in human VSMCs were examined by Western blot analysis, real-time PCR, in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and enzyme-linked immunosorbent assay, respectively. Increase in VSMC calcification in human atherosclerotic plaques upregulates MGP expression and apoptosis in a negative feedback manner. ANG II inhibited MGP expression in VSMCs via and in vitro in a dose- and time-dependent manner through ANG II type 1 receptor and NF-κB signaling pathway. Meanwhile, MGP inhibited the calcification, caspase-3 activity, activation of runt-related transcription factor 2, and release of inflammatory cytokines by VSMCs induced by calcification medium (2.5 mM P(i)) and ANG II in vitro. These observations provide evidence that ANG II exacerbates vascular calcification through activation of the transcription factors, runt-related transcription factor 2 and NF-κB, and regulation of MGP, inflammatory cytokines expression in human VSMCs.
Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Guanghong
G
Jia
Ryan M
RM
Stormont
Deepak M
DM
Gangahar
Devendra K
DK
Agrawal
D000368:Aged; D000804:Angiotensin II / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002130:Calcium Phosphates / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D061205:Vascular Calcification / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000097568:Matrix Gla Protein
D000804:Angiotensin II; D002130:Calcium Phosphates; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D050659:Core Binding Factor Alpha 1 Subunit; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D000097568:Matrix Gla Protein; C544065:AGTR1 protein, human; C493709:RUNX2 protein, human; C020243:calcium phosphate; C505407:CASP3 protein, human