title: Hyperhomocysteinemia decreases intestinal motility leading to constipation.
abstract: Elevated levels of plasma homocysteine (Hcy) called hyperhomocysteinemia (HHcy) have been implicated in inflammation and remodeling in intestinal vasculature, and HHcy is also known to aggravate the pathogenesis of inflammatory bowel disease (IBD). Interestingly, colon is the pivotal site that regulates Hcy levels in the plasma. We hypothesize that HHcy decreases intestinal motility through matrix metalloproteinase-9 (MMP-9)-induced intestinal remodeling leading to constipation. To verify this hypothesis, we used C57BL/6J or wild-type (WT), cystathionine β-synthase (CBS(+/-)), MMP-9(-/-), and MMP-9(-/-) + Hcy mice. Intestinal motility was assessed by barium meal studies and daily feces output. Plasma Hcy levels were measured by HPLC. Expression of ICAM-1, inducible nitric oxide synthase, MMP-9, and tissue inhibitors of MMPs was studied by Western blot and immunohistochemistry. Reactive oxygen species (ROS) including super oxide were measured by the Invitrogen molecular probe method. Tissue nitric oxide levels were assessed by a commercially available kit. Plasma Hcy levels in the treated MMP-9 group mice were comparable to CBS(+/-) mice. Barium meal studies suggest that intestinal motility is significantly decreased in CBS(+/-) mice compared with other groups. Fecal output-to-body weight ratio was significantly reduced in CBS(+/-) mice compared with other groups. There was significant upregulation of MMP-9, iNOS, and ICAM-1 expression in the colon from CBS(+/-) mice compared with WT mice. Levels of ROS, superoxide, and inducible nitric oxide were elevated in the CBS(+/-) mice compared with other groups. Results suggest that HHcy decreases intestinal motility due to MMP-9-induced intestinal remodeling leading to constipation.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. s0givv01@louisville.edu
authors.forename: S
authors.initials: S
authors.lastname: Givvimani
authors.forename: C
authors.initials: C
authors.lastname: Munjal
authors.forename: N
authors.initials: N
authors.lastname: Narayanan
authors.forename: F
authors.initials: F
authors.lastname: Aqil
authors.forename: G
authors.initials: G
authors.lastname: Tyagi
authors.forename: N
authors.initials: N
authors.lastname: Metreveli
authors.forename: S C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D003106:Colon / Q000502:physiology*; D003248:Constipation / Q000209:etiology*; D003541:Cystathionine beta-Synthase / Q000235:genetics; D005243:Feces; D005769:Gastrointestinal Motility / Q000187:drug effects*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
chemical_list: C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020780:Matrix Metalloproteinase 9; D003541:Cystathionine beta-Synthase