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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Koenig, James I
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Massachusetts General Hospital
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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
Tanigaki, Keiji; Vongpatanasin, Wanpen; Barrera, Jose A et al. (2013) C-reactive protein causes insulin resistance in mice through Fc? receptor IIB-mediated inhibition of skeletal muscle glucose delivery. Diabetes 62:721-31
Kashiwagi, Satoshi; Atochin, Dmitriy N; Li, Qian et al. (2013) eNOS phosphorylation on serine 1176 affects insulin sensitivity and adiposity. Biochem Biophys Res Commun 431:284-90
Ayata, Cenk; Shin, Hwa Kyoung; Dilekoz, Ergin et al. (2013) Hyperlipidemia disrupts cerebrovascular reflexes and worsens ischemic perfusion defect. J Cereb Blood Flow Metab 33:954-62
Pointer, Mildred A; Daumerie, Geraldine; Bridges, LaKessha et al. (2012) Physiological stress increases renal injury in eNOS-knockout mice. Hypertens Res 35:318-24
Chernigovskaya, E; Atochin, D; Yamova, L et al. (2011) Immunohistochemical expression of Bcl-2, p53 and caspase-9 in hypothalamus magnocellular centers of nNOS knockout mice following water deprivation. Biotech Histochem 86:333-9
Srinivasan, Vivek J; Atochin, Dmitriy N; Radhakrishnan, Harsha et al. (2011) Optical coherence tomography for the quantitative study of cerebrovascular physiology. J Cereb Blood Flow Metab 31:1339-45
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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