Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 56, Issue 2, Pages 301-307Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2009.11.002
Keywords
Blood-brain barrier; Tissue inhibitors of matrix; metalloproteinases; Cystathionine-beta-synthase (CBS); Cystathionine-gamma-lyase (CSE)
Categories
Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL074185, R01HL088012, R01HL071010] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS051568] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL074185-07, R01 HL071010-08, R01 HL088012-04, R01 HL071010, R01 HL074185, HL-88012, R01 HL088012, HL-71010, HL-74185] Funding Source: Medline
- NINDS NIH HHS [R01 NS051568, R01 NS051568-05, NS-51568] Funding Source: Medline
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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 mu M/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. (C) 2009 Elsevier Ltd. All rights reserved.
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