title: Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity.
abstract: OBJECTIVE
  Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD(+), niacin could elicit these vascular benefits through NAD(+)-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved.
  
  
  RESULTS
  Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD(+) precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD(+) and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin.
  
  
  CONCLUSIONS
  Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD(+) biosynthesis and SIRT1 activation, but rather through niacin receptor activation.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Hughes-Large
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Dominic K T
authors.initials: DK
authors.lastname: Pang
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Robson
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Pak
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Toma
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada. Electronic address: nica.borradaile@schulich.uwo.ca.
authors.forename: Nica M
authors.initials: NM
authors.lastname: Borradaile
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D002417:Cattle; D016923:Cell Death; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D024821:Metabolic Syndrome / Q000378:metabolism; D008833:Microcirculation; D009243:NAD / Q000737:chemistry; D009525:Niacin / Q000737:chemistry*; D009537:Nicotinamide Mononucleotide / Q000737:chemistry; D009765:Obesity / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry
chemical_list: C573553:1a,3,5,5a-tetrahydro-1H-2,3-diazacyclopropa(a)pentalene-4-carboxylic acid; D004338:Drug Combinations; C530636:HCAR2 protein, human; D007797:Laminin; D008055:Lipids; D011509:Proteoglycans; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D012709:Serum Albumin; D009243:NAD; D009537:Nicotinamide Mononucleotide; C059485:matrigel; D009525:Niacin; D003094:Collagen
keywords: Fatty acids; Lipids; Metabolic syndrome; Obesity; Vascular disease