title: Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice.
abstract: An elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), was associated with neurovascular diseases. At physiological levels, hydrogen sulfide (H(2)S) protected the neurovascular system. Because Hcy was also a precursor of hydrogen sulfide (H(2)S), we sought to test whether the H(2)S protected the brain during HHcy. Cystathionine-beta-synthase heterozygous (CBS+/-) and wild type (WT) mice were supplemented with or without NaHS (30 microM/L, H(2)S donor) in drinking water. Blood flow and cerebral microvascular permeability in pial vessels were measured by intravital microscopy in WT, WT+NaHS, CBS-/+ and (CBS-/+)+NaHS-treated mice. The brain tissues were analyzed for matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) by Western blot and RT-PCR. The mRNA levels of CBS and cystathionine gamma lyase (CSE, enzyme responsible for conversion of Hcy to H(2)S) genes were measured by RT-PCR. The results showed a significant increase in MMP-2, MMP-9, TIMP-3 protein and mRNA in CBS (-/+) mice, while H(2)S treatment mitigated this increase. Interstitial localization of MMPs was also apparent through immunohistochemistry. A decrease in protein and mRNA expression of TIMP-4 was observed in CBS (-/+) mice. Microscopy data revealed increase in permeability in CBS (-/+) mice. These effects were ameliorated by H(2)S and suggested that physiological levels of H(2)S supplementation may have therapeutic potential against HHcy-induced microvascular permeability, in part, by normalizing the MMP/TIMP ratio in the brain.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA. n0tyag01@louisville.edu
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.forename: Natia
authors.initials: N
authors.lastname: Qipshidze
authors.forename: Soumi
authors.initials: S
authors.lastname: Kundu
authors.forename: Shray
authors.initials: S
authors.lastname: Kapoor
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Vacek
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000503:physiopathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020780:Matrix Metalloproteinase 9; D006862:Hydrogen Sulfide