Our recent studies show that insulin resistance (IR) severely impairs arterial dilator function in the cerebral circulation via mechanisms involving the sustained production and actions of reactive oxygen species (ROS). Our overall hypothesis is that: Vascular dysfunction of the cerebral circulation in IR is due to augmented ROS levels from enhanced activity of the NADPH oxidase system. Furthermore, we speculate that differences are present in ROS signaling occur in endothelium and VSM; that statins directly modulate NADPH oxidase activity or indirectly act via a reduction in vascular inflammation; that ROS scavenging by superoxide dismutase or gene transfer of EcSOD reverses vascular dysfunction; that neurological damage is enhanced in IR; and that acute administration of statins can limit IR-enhanced ischemic damage in IR. We have created 2 specific aims to test the following hypotheses and speculations in the cerebral circulation and brain in a genetic model of IR (Zucker obese rats):
Specific Aim 1. Elucidation of mechanisms of deranged arterial function of the cerebral circulation in IR. We will test the hypothesis that IR impairs endothelium- and VSM potassium channel-dependent function of cerebral arteries via vascular production and actions of ROS. First, we will assess the role of ROS in vascular dysfunction in IR using pharmacological agents and gene transfer approaches. Second, we will determine the metabolic source and characteristics of ROS involved in dysfunction of cerebral vessels of IR rats. Third, we will document, using electrophysiological approaches, the effects of ROS on potassium channels-dependent membrane potential characteristics in cerebral arteries from IR rats. Fourth, we will examine the effects of IR on extent of neurological injury following experimental strokes.
Specific Aim 2. Examination of mechanism of statins in reversing vascular dysfunction in IR. We will test the hypothesis that statins directly modulate NADPH oxidase activity in IR. First, we will assess the dynamics of statin effects on vascular responsiveness in IR. Second, we will determine the effects of statins on indices of vascular inflammation and ROS production in cerebral arteries. Third, we will examine the effects of statins and IR on VSM membrane characteristics. Fourth, we will examine the effects of statins on the extent of stroke damage in IR. We believe that our results will lead to new therapies that will help patients with insulin resistance and vascular dysfunction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065380-06
Application #
7406037
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2000-07-01
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$313,512
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G et al. (2015) The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Nautiyal, Manisha; Katakam, Prasad V G; Busija, David W et al. (2012) Differences in oxidative stress status and expression of MKP-1 in dorsal medulla of transgenic rats with altered brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 303:R799-806
Institoris, Adam; Lenti, Laura; Domoki, Ferenc et al. (2012) Cerebral microcirculatory responses of insulin-resistant rats are preserved to physiological and pharmacological stimuli. Microcirculation 19:749-56
Katakam, Prasad V G; Snipes, James A; Steed, Mesia M et al. (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792-804

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