Hypertension Affinity Group
The Cardiovascular Center has initiated AFFINITY GROUPS to stimulate and foster greater interaction and collaborations between CVC investigators and other investigators from MCW departments and outside institutions, such as Marquette University, the University of Wisconsin Milwaukee and the University of Georgia.
Essential hypertension affects more than 50 million Americans and increased blood pressure salt-sensitivity is a prominent feature in certain populations of hypertensive patients, especially hypertensive African Americans who also exhibit a significantly higher risk of end organ renal damage. Although it is evident that the common forms of hypertension are multifactorial (polygenic and environmental), little significant progress has been made in identifying the specific genetic basis of human hypertension. Defining the physiological and genetic basis of common forms of human hypertension, however, remains a great challenge.
There is a broad interest related to the field of hypertension at MCW that is supported by several programmatic initiatives and a number of individual research grants. One Program Project Grant, which includes Allen W. Cowley, Jr., PhD, Howard Jacob, PhD, Carol Moreno-Quinn, MD, PhD, Mingyu Liang, PhD, and Andrew Greene, PhD, and is supported by the National Institutes of Health (NIH), is focused upon understanding the genetic regulation of the complex pathways regulating arterial pressure, the overriding challenge in the field of hypertension research. This program utilizes rat genetic model systems to advance our understanding of the complex regulation and interplay of a set of genes residing in two different regions of rat chromosome 13, which together are responsible in large measure for salt-induced hypertension, renal injury, and reduced blood vessel density of the microcirculation. This rat strain develops severe hypertension when placed on a high salt diet (Dahl salt-sensitive rat) and exhibits many of the same traits found in human forms of salt-sensitive hypertension. The uniqueness and strength of this program is that it is designed to explore the integrated genomic, cellular, tissue, organ, and whole animal components of hypertension. This multi-scale approach brings together an interdisciplinary team of experts in genomics/genetics, proteomics, bioinformatics/ computational biology, and cell/organ/whole animal physiology required to study this complex disease at levels that no one has yet attempted.
A second Program Project Grant, comprised of Drs. Allen Cowley and Mingyu Liang, and David Mattson, PhD, and Richard Roman, PhD, is focused upon the role of the kidney in hypertension and explores the physiological mechanisms responsible for the salt-induced renal dysfunction and hypertension found in the Dahl salt-sensitive rat model of hypertension. One of the projects hypothesizes that a high salt diet results in greater tubular sodium reabsorption in the outer medulla of the kidney in salt-sensitive rats and thereby stimulates excess production of reactive oxygen species (ROS) in the renal medullary thick ascending limb (mTAL). It is proposed that this will reduce medullary blood flow and drive the initial rise of arterial pressure during the first week of hypertension. Another project hypothesizes that an inflammatory process develops within the renal inner cortex and outer medulla that is initiated by infiltrating macrophages that produce angiotensin II. This further stimulates ROS production and renal injury.
A third project focuses on defining a mutation in one of the cytochrome P4504A genes (CYP4A) responsible for renal 20-HETE production and proposes that this genetic defect plays an important causal role in impaired pressure natriuresis, sodium retention, and the development of hypertension.
In closely related NIH-supported studies, Julian Lombard, PhD and Dr. Andrew Greene carry out studies to determine why a high salt intake leads to a dramatic reduction in small vessel density in a number of organs, and why it leads to a reduced ability of larger blood vessels to relax, both of which result in reduced blood flow to critical organs even in the absence of hypertension. A number of studies are under way to determine the mechanisms responsible for these important observations and particularly for the role played by the renin-angiotensin system and vascular oxidative stress.
In another important area of research related to hypertension, William Campbell, PhD and John Imig, PhD, focus on the elucidation of mechanisms whereby epoxyeicosatrienoic acids (EETs) and the epoxide hydrolase enzyme influence renal and cerebral vascular function in hypertension. Newly developed, highly selective epoxide hydrolase inhibitors are being assessed to determine their ability to lower arterial blood pressure and improve renal vascular function and decrease stroke-induced brain damage in hypertension.
Cardiovascular Annual Report 2010
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