title: Intermedin inhibits vascular calcification by increasing the level of matrix gamma-carboxyglutamic acid protein.
abstract: OBJECTIVE
  Vascular calcification (VC) is highly associated with increased morbidity and mortality in patients with advanced chronic kidney disease. Paracrine/autocrine factors such as vasoactive peptides are involved in VC development. Here, we investigated the expression of the novel peptide intermedin (IMD) in the vasculature, tested its ability to prevent VC in vivo and in vitro, and examined the mechanism involved.
  
  
  RESULTS
  Rat VC was induced by administration of vitamin D3 plus nicotine (VDN). IMD (100 ng kg(-1) h(-1)) was systemically administered by a mini-osmotic pump. VDN-treated rat aortas showed lower IMD content and increased expression of its receptors, along with increased vascular calcium deposition and alkaline phosphatase (ALP) activity. Low IMD levels were accompanied by increased calcium deposition in human atherosclerotic plaques. In vivo administration of IMD greatly reduced vascular calcium deposition and ALP activity in VDN-treated rats when compared with vehicle treatment, which was further confirmed in cultured vascular smooth muscle cells. Concurrently, the loss of smooth-muscle lineage markers and matrix gamma-carboxyglutamic acid (Gla) protein (cMGP) in aortas was ameliorated by administering IMD to rats with VC, and the increased phosphor-Smad(1/5/8) and core binding factor alpha-1 levels in calcified vasculature were also reduced. However, the inhibitory effects of IMD on VC were eliminated upon pre-treatment with warfarin or small interfering RNA to reduce cMGP.
  
  
  CONCLUSIONS
  Reduced endogenous IMD levels are associated with increased mineralization in vivo, and administration of IMD inhibits VC development by increasing cMGP levels. IMD may be an endogenous vasoprotective factor for VC.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.forename: Xu
authors.initials: X
authors.lastname: Teng
authors.forename: Ye Bo
authors.initials: YB
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Chao Shu
authors.initials: CS
authors.lastname: Tang
authors.forename: Yong Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000633:toxicity; D018722:Nicotinic Agonists / Q000633:toxicity; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D014807:Vitamin D / Q000633:toxicity; D014815:Vitamins / Q000633:toxicity; D000097568:Matrix Gla Protein
chemical_list: D053607:Adrenomedullin; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D009479:Neuropeptides; D009538:Nicotine; D018722:Nicotinic Agonists; D036361:Peptide Hormones; D051785:Smad Proteins; D014807:Vitamin D; D014815:Vitamins; D000097568:Matrix Gla Protein; C484330:ADM2 protein, human; C499411:Adm2 protein, rat