Cytochrome P450-4A (CYP450-4A) w-hydroxylase, which catalyzes the formation of 20-hydroxy- eicosatetraenoic acid (20-HETE) from arachidonic acid, may act as a vascular O2 sensor, with a crucial role n regulating vascular tone during both increases and decreases in O2 availability. Our studies indicate that enhanced activity of the CYP450-20-HETE system is a major candidate to elevate vascular resistance during the development of salt sensitive forms of hypertension by sensing O2 availability and mediating O2- dependent vasoconstriction in the peripheral circulation. This proposal represents a continuation of a successful line of studies investigating the role of 20-HETE and CYP450-4A w-hydroxylase in mediating altered responses to changes in O2 availability in the Dahl salt-sensitive (SS) rat. The overall hypothesis to be tested in this study is that the enhanced response of arterioles to elevated PO2 in Dahl SS hypertensive rats is due to one or a combination of three factors: increases in the production of 20-HETE, an increased sensitivity of the vessels to the vasoconstrictor effects of 20-HETE, and/or an altered expression of cytochrome P450-4A w-hydroxylase, the enzyme that catalyzes the synthesis of 20-HETE from arachidonic acid. To test this hypothesis, the proposed study has the following Specific Aims: 1) To utilize consomic and congenic rat models to evaluate the role of cytochrome P450 (CYP450) enzymes and 20-HETE in contributing to altered vascular O2 responses in SS rats on high salt (HS) diet;2) To determine whether HS diet changes the expression pattern of individual P450-4A w-hydroxylase isoforms and increases CYP- 4504A protein expression in arterioles and resistance arteries of SS rats;3): To determine whether 20-HETE production is elevated in arterioles and resistance arteries of SS rats on HS diet compared to normotensive SS rats on LS diet and rat strains lacking the SS CYP450-4A alleles;and 4) To determine whether HS diet increases 20-HETE sensitivity in arterioles of SS rats, and whether any salt-induced potentiation of arteriolar 20-HETE sensitivity is prevented by introgression of CYP450 genes from rat strains lacking the SS CYP450- 4A alleles. These studies should provide valuable insight into how vascular control mechanisms are altered during salt-sensitive hypertension in humans, particularly in members of the African-American population, who exhibit a form of salt sensitive hypertension that is strikingly similar to that occurring in the Dahl SS rat.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072920-09
Application #
8044792
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2003-04-01
Project End
2012-09-30
Budget Start
2011-04-01
Budget End
2012-09-30
Support Year
9
Fiscal Year
2011
Total Cost
$341,449
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Lukaszewicz, Kathleen M; Paudyal, Mahesh P; Falck, John R et al. (2016) Role of vascular reactive oxygen species in regulating cytochrome P450-4A enzyme expression in Dahl salt-sensitive rats. Microcirculation 23:540-548
Beyer, Andreas M; Raffai, Gabor; Weinberg, Brian D et al. (2014) Amelioration of salt-induced vascular dysfunction in mesenteric arteries of Dahl salt-sensitive rats by missense mutation of extracellular superoxide dismutase. Am J Physiol Heart Circ Physiol 306:H339-47
Lukaszewicz, Kathleen M; Lombard, Julian H (2013) Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat. Clin Sci (Lond) 124:695-700
Lukaszewicz, Kathleen M; Falck, John R; Manthati, Vijaya L et al. (2013) Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5(BN) consomic rats. Clin Sci (Lond) 124:333-42
Priestley, Jessica R C; Buelow, Matthew W; McEwen, Scott T et al. (2013) Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles. Microvasc Res 89:134-45
Beyer, Andreas M; Raffai, Gabor; Weinberg, Brian et al. (2012) Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity. Hypertension 60:404-10
Raffai, Gabor; Durand, Matthew J; Lombard, Julian H (2011) Acute and chronic angiotensin-(1-7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats. Am J Physiol Heart Circ Physiol 301:H1341-52
Drenjancevic-Peric, I; Jelakovic, B; Lombard, J H et al. (2011) High-salt diet and hypertension: focus on the renin-angiotensin system. Kidney Blood Press Res 34:1-11
Durand, Matthew J; Moreno, Carol; Greene, Andrew S et al. (2010) Impaired relaxation of cerebral arteries in the absence of elevated salt intake in normotensive congenic rats carrying the Dahl salt-sensitive renin gene. Am J Physiol Heart Circ Physiol 299:H1865-74
Durand, Matthew J; Raffai, Gábor; Weinberg, Brian D et al. (2010) Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 299:H1024-33

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