Role of PPAR-gamma in Cerebral Endothelium

Summary

Principal Investigator: Frank M Faraci
Abstract: DESCRIPTION (provided by applicant): Because it is a major risk factor for cerebrovascular disease and stroke and a leading cause of cognitive decline, hypertension has an enormous negative impact on the brain. End-organ damage to endothelium underlies many forms of cerebrovascular disease with diverse consequences. The renin-angiotensin sys- tem (RAS) and angiotensin II (Ang II) play a fundamental role during hypertension and in the pathogenesis of vascular disease. Detrimental effects of the RAS are commonly due to Ang II acting on AT1 receptors resulting in activation of many downstream targets and oxidative stress. A major barrier to progress for preventing cerebrovascular disease has been our limited understanding of endogenous molecules and pathways that may effectively suppress these processes. Our pilot data suggest the transcription factor peroxisome proliferator-activated receptor- (PPAR) has a major influence on the cerebral circulation with links to the RAS. Using novel mouse models to define cell-specific mechanisms, our overall goal is to determine if endothelial PPAR protects the vasculature in Ang II-dependent models of disease and to define targets or pathways that mediate these effects. To define the role of PPAR in this cell type, we will examine the hypothesis that interference with endothelial PPAR augments Ang-II induced vascular dysfunction and abnormal vascular growth (Aim 1). As part of this Aim we will also determine if increased expression of wild-type PPAR in endothelium protects against detrimental structural and functional effects. Our preliminary data suggest genetic interference with endothelial PPAR increases expression of NADPH oxidase and augments Ang II-induced vascular dysfunction while increased endothelial expression of wild- type PPAR inhibits vascular effects of Ang II. In contrast to Ang II, the RAS can exert beneficial effects via the actions of Ang (1-7). Aim 2 will unravel a previously unknown interaction and determine if Ang (1-7) and its receptor are targets of endothelial PPAR. We will determine if interference with endothelial PPAR impairs vascular effects of the Ang (1-7) arm of the RAS and define mechanisms involved. Our preliminary data support this hypothesis. We suggest PPAR and select targets in endothelium are part of a previously unrecognized mechanism that suppresses detrimental effects of Ang II. The balance between PPAR and the RAS (and their respective targets) in endothelium may be a major determinant of the onset and pro- gression of carotid and cerebrovascular disease. Defining key connections between PPAR and the RAS may ultimately lead to more specific therapeutic targeting for vascular disease that leads to stroke and/or contributes to the vascular component of Alzheimers disease and hypertension-induced cognitive impairment.
Funding Period: 2013-07-01 - 2017-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Cardiac function as a mechanism for maladaptive brain aging
    Angela L Jefferson; Fiscal Year: 2013
    ....
  2. Vitamin D, cerebrovascular risk, and neurocognitive decline: ARIC Brain MRI Study
    Erin D Michos; Fiscal Year: 2013
    ....
  3. CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE
    Costantino Iadecola; Fiscal Year: 2013
    ..Ultimately, the results of the proposed studies may suggest novel mechanism-based approaches to prevent or treat the deleterious effects of this highly prevalent condition. ..