Homocysteine decreases blood flow to the brain due to vascular resistance in carotid artery.
An elevated level of Homocysteine (Hcy) is a risk factor for vascular dementia and stroke. Cysthathionine beta Synthase (CBS) gene is involved in the clearance of Hcy. Homozygous individuals for (CBS-/-) die early, but heterozygous for (CBS-/+) survive with high levels of Hcy. The gamma-Amino Butyric Acid (GABA) presents in the central nervous system (CNS) and functions as an inhibitory neurotransmitter. Hcy competes with GABA at the GABA(A) receptor and affects the CNS function. We hypothesize that Hcy causes a decrease in blood flow to the brain due to increase in vascular resistance (VR) because of arterial remodeling in the carotid artery (CA). Blood pressure and blood flow in CA of wild type (WT), CBS-/+, CBS-/+ GABA(A)-/- double knockout, and GABA(A)-/- were measured. CA was stained with trichrome, and the brain permeability was measured. Matrix Metalloproteinases (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase (TIMP-3, TIMP-4), elastin, and collagen-III expression were measured by real-time polymerase chain reaction (RT-PCR). Results showed an increase in VR in CBS-/+/GABA(A)-/-double knockout>CBS-/+/>GABA(A)-/- compared to WT mice. Increased MMP-2, MMP-9, collagen-III and TIMP-3 mRNA levels were found in GABA(A)-/-, CBS-/+, CBS-/+/GABA(A) double knockout compared to WT. The levels of TIMP-4 and elastin were decreased, whereas the levels of MMP-2, MMP-9 and TIMP-3 increased, which indirectly reflected the arterial resistance. These results suggested that Hcy caused arterial remodeling in part, by increase in collagen/elastin ratio thereby increasing VR leading to the decrease in CA blood flow.
Kumar
Munish
M
Department of Physiology & Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Tyagi
Neetu
N
Moshal
Karni S
KS
Sen
Utpal
U
Kundu
Soumi
S
Mishra
Paras K
PK
Givvimani
Srikanth
S
Tyagi
Suresh C
SC
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000378:metabolism*; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004549:Elastin / Q000235:genetics / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism* / Q000633:toxicity; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D024061:Collagen Type III; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D019714:Tissue Inhibitor of Metalloproteinases; D006710:Homocysteine; D005680:gamma-Aminobutyric Acid; D003094:Collagen; D004549:Elastin; D020782:Matrix Metalloproteinases; D003541:Cystathionine beta-Synthase