title: Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1.
abstract: Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 and ADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling.
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Sathnur
authors.initials: S
authors.lastname: Pushpakumar
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Doyle
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Nithya
authors.initials: N
authors.lastname: Narayanan
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Winchester
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Veeranki
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.affiliation: Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.|Department of Physiology & Biophysics, School of Medicine, University of Louisville, KY 40202, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000581:Amidohydrolases / Q000096:biosynthesis; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000096:biosynthesis; D043303:Aryldialkylphosphatase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D017630:Connexins / Q000096:biosynthesis; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D020138:Hyperhomocysteinemia / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000503:physiopathology; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
chemical_list: D000581:Amidohydrolases; D001120:Arginine; D043303:Aryldialkylphosphatase; D017630:Connexins; D008075:Lipoproteins, HDL; D020780:Matrix Metalloproteinase 9; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein; C018524:N,N-dimethylarginine; C496315:Nos3 protein, mouse; C560867:PON1 protein, mouse; C059999:dimethylargininase
keywords: Akt; Cx-37 and -40; MMP-9; atherosclerosis; athérosclérose; connexines 37 et 40; eNOS; homocysteine; homocystéine