Role of 20-HETE on aging and hypertension related cerebral vascular disease

Hypertension is the leading risk factor for the development of stroke, VCI and Alzheimer's disease. The incidence of hypertension is increased with aging. About 29%American adults have hypertension and 40% of VCI patients suffer from this disease. The costs for the treatment of hypertension exceed 46billion/year.Dementiacoststhenation159 billion and is projected to rise to $511 billion each year by 2040. This will dwarf the entire NIH budget and highlights the urgency to better develop strategies for the prevention and treatment of related diseases. Evidence suggests that the myogenic response and autoregulation of CBF are often impaired in elderly hypertensive individuals; however, the mechanism involved is still obscure; part of the reason has been the lack of appropriate genetic animal models. This proposal will characterize our newly developed animal models to investigate the role of CYP4A and 20-HETE in the contribution of aging and hypertension related cerebral vascular disease in Dahl SS rats. We first reported that SS rats have impaired myogenic response and fail to autoregulate CBF. Preliminary data suggested that SS rats exhibit characteristics of VCI such as vascular remodeling, BBB leakage, neurodegeneration, and cognitive impairments following the development of hypertension. More recently, we first discovered that functional variants of CYP4A11 and CYP4F2, genes that produce 20-HETE in human, are not only associated with hypertension and stroke as previously reported, but also linked to cognitive impairments in 3,649 elderly hypertensive patients from the ARIC-NCS study. Based on this evidence, we hypothesize that reduced levels of CYP4A and 20-HETE play an important role in the impaired myogenic response and autoregulation of CBF, and contribute to the development of aging and hypertension related VCI. The proposed studies aim to utilize our novel genetic animal model to study the mechanisms by which impairments of CBF autoregulation lead to neurodegeneration and cognitive decline that are commonly seen in elderly and hypertensive individuals. This proposal is clearly distinct from ongoing research activities currently funded in our group. The studies will provide proof of principal data to support the hypothesis for the PI to submit a RO1 grant application as a new investigator to further study the mechanisms involved. (AHA Program: Grant-in-Aid)