application) The investigator's overall hypothesis is that physiologic production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) suppresses atherosclerosis, whereas pathologic production of NO by inducible NOS (iNOS) and neuronal NOS (nNOS) contributes to atherosclerosis. In order to test this hypothesis, it is necessary to separate the effects of the various NOS isoforms. Pharmacologic approaches are limited because NOS inhibitors, NO donors, and NO precursors do not distinguish between the isoforms. The investigator plans to use NOS knockout mice as specific tools to dissect out the roles of each NOS isoform in the molecular events of atherosclerosis. To study the cellular proliferative response, the investigator plans to quantify the response of NOS mutant mice to two well-defined models of vascular injury: cuff induced adventitial injury of the femoral artery, and filament induced endothelial injury of the carotid artery. To study the development of complex atherosclerotic lesions, the investigator will use apoE mutant mice as a model system. The investigator will generate double knockout mice that lack apoE and each NOS isoform to determine the effect of each isoform on apoE- deficiency atherosclerosis. To study the effects of NO on the molecular events that underlie atherogenesis, the investigator will determine which NOS isoform(s) is involved in peroxynitrite generation, and test whether peroxynitrite is essential for lipid peroxidation and endothelial cell activation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057818-05
Application #
6490577
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Applebaum-Bowden, Deborah
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
5
Fiscal Year
2002
Total Cost
$241,513
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41
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
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
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
Zhang, Xiuqin; Zhang, Rongli; Raab, Susanne et al. (2011) Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone. Circulation 124:77-86
Daumerie, Geraldine; Bridges, Lakeesha; Yancey, Sadiqa et al. (2010) The effect of salt on renal damage in eNOS-deficient mice. Hypertens Res 33:170-6
Kuhlencordt, Peter J; Padmapriya, P; Rützel, S et al. (2009) Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS-deficient ApoE ko mice. Atherosclerosis 202:48-57
Schödel, Johannes; Padmapriya, P; Marx, Alexander et al. (2009) Expression of neuronal nitric oxide synthase splice variants in atherosclerotic plaques of apoE knockout mice. Atherosclerosis 206:383-9
Liu, Victor W T; Huang, Paul L (2008) Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 77:19-29
Yamova, Liubov; Atochin, Dmitriy; Glazova, Margarita et al. (2007) Role of neuronal nitric oxide in the regulation of vasopressin expression and release in response to inhibition of catecholamine synthesis and dehydration. Neurosci Lett 426:160-5

Showing the most recent 10 out of 28 publications