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Epigenetic Regulation of Cerebrovascular Remodeling Mediated Through Exosomes in Hyperhomocysteinemia: Role of Folic Acid
Author(s) -
Kalani Anuradha,
Narayanan Nithya,
Qipshidze Natia,
Givvimani Srikanth,
Kamat Pradip K.,
Tyagi Suresh C.,
Tyagi Neetu
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.932.9
Subject(s) - methyltransferase , oxidative stress , hyperhomocysteinemia , homocysteine , endocrinology , medicine , matrix metalloproteinase , blood–brain barrier , cystathionine beta synthase , epigenetics , biology , chemistry , biochemistry , methylation , central nervous system , amino acid , methionine , gene
An elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is associated with neurovascular diseases. HHcy induces oxidative stress that may epigenetically mediate cerebrovascular remodeling. It has been recently shown that exosomes may induce epigenetic changes and affect brain functions. However, the mechanisms behind such alterations remain unclear. The present study examined whether cerebrovascular remodeling is mediated through exosomes and improved epigenetically with folic acid (FA) treatment. To test this hypothesis we employed 8 weeks old male wild type (WT), cystathionine‐beta‐synthase heterozygote knockout (CBS+/‐), WT + FA, CBS (+/‐) +FA (0.0057 μg/g/day dose in drinking water/4weeks) mice. Microvascular permeability in pial vessels was measured by intravital microscopy. The brain tissues were analyzed for matrix metalloproteinases, tissue inhibitor of metalloproteinases, oxidative stress, Hcy metabolic enzymes by western blot, qRT‐PCR, IF and HPLC. Microvascular permeability, MMP‐2–9 and gp‐91(oxidant) were increased while TIMP‐1,‐4, tight junction proteins, MTHFR, SAHH and DNA methyltransferases were decreased in CBS (+/‐) mice as compared to WT. Interestingly, cerebrovascular remodeling/epigenetic markers were also altered on exosomes from CBS (+/‐) mice as compared to WT. Thus, cerebrovascular remodeling, mediated through exosomes, is significantly improved with FA treatment in CBS (+/‐) mice showing its potential therapeutic role against HHcy related pathologies.