Nitric oxide (NO) plays an important role in normal and pathological cerebrovascular functioning, including regulation of cerebral blood flow, and maintenance of perfusion during ischemia in the core and penumbral areas. In mice with diabetes (db/db) or atherosclerosis (apoE ko ) there is diminished phosphorylation of eNOS at the critical S1179 site. The investigators have generated ki mice carrying phosphomimetic (S1179D) and unphophorylatable (S1179A) forms of eNOS, in control, db/db and apoE-ko mice.
They aim to prove that modulation of the S1179 eNOS phosphorylation site can influence vascular function under normal and pathological circumstances, and that improved phosphorylation improves cv reactivity in vivo and outcome in stroke in animals with diabetes and stroke.

Public Health Relevance

The investigators have a long history of studying how known cardiovascular risk factors such as high blood pressure, diabetes and hypercholesterolemia lead to increased risk for stroke (and MI). Although it is already known that risk factors are associated with diminished phosphorylation at the S1179 site, while "risk antagonists", such as statins, insulin etc. are associated with increased phophorylation, the investigators can tease out with their very clever models what is simply association and what is causative. This may well lead to the development of new treatment options directly addressing the links between metabolic diseases and (cerebro)vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033335-18
Application #
8286414
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Koenig, James I
Project Start
1994-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$340,778
Indirect Cost
$126,403
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Shin, Hwa Kyoung; Huang, Paul L; Ayata, Cenk (2014) Rho-kinase inhibition improves ischemic perfusion deficit in hyperlipidemic mice. J Cereb Blood Flow Metab 34:284-7
Pong, Terrence; Scherrer-Crosbie, Marielle; Atochin, Dmitriy N et al. (2014) Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice. PLoS One 9:e85946
Li, Qian; Atochin, Dmitriy; Kashiwagi, Satoshi et al. (2013) Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size. Stroke 44:3183-8
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Atochin, Dmitriy N; Yuzawa, Izumi; Li, Qian et al. (2010) Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury. Stroke 41:1815-9

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