High salt (HS) diet leads to a dramatic and widespread impairment of vascular relaxation mechanisms and an impaired ability to regulate tissue perfusion in the absence of an elevated blood pressure. Angiotensin II (ANG II) suppression in response to HS diet is a crucial factor contributing to impaired vascular relaxation, since this effect can be prevented by chronic i.v. infusion of a subpressor dose of ANG II to prevent salt-induced suppression of plasma ANG II. An unexpected finding is that impaired vascular relaxation in rats fed HS diet is accompanied by an increased level of oxidative stress that can also be prevented by ANG II infusion. This action of ANG II appears to be mediated via transactivation of the EGF receptor, because it can be mimicked by infusion of EGF, and the protective effect of both ANG II and EGF to restore vascular relaxation in animals on HS diet can be prevented by inhibiting the EGF receptor or the ERK 1/2 pathway. The goal of this renewal application is to elucidate the mechanisms by which ANG II restores vascular relaxation in rats fed HS diet (with special emphasis on the role of EGF receptor transactivation and the ERK 1/2 pathway in maintaining vascular relaxation and normal antioxidant defense mechanisms). Our fundamental hypothesis is that impaired vascular relaxation in rats fed HS diet is due to an increase in vascular oxidative stress resulting from down regulation of antioxidant enzymes such as copper/zinc superoxide dismutase (Cu/Zn SOD), and possibly upregulation of pro- oxidant enzymes. We further hypothesize that ANG II exerts its protective effect to maintain normal vascular relaxation via transactivation of the EGF receptor, leading to increased expression of antioxidant enzymes, e.g., Cu/Zn SOD.
The Specific Aims of this project are to: 1) evaluate the role of ANG II and EGF receptor transactivation in preventing oxidative stress and maintaining normal vascular relaxation mechanisms via the ERK 1/2 pathway;2), evaluate the role of ANG II and EGF receptor transactivation in regulating the expression of pro- and antioxidant enzymes via the ERK 1/2 pathway;and 3) evaluate pro- and anti-oxidant enzyme activity in vessels from rats fed LS and HS diet, and to determine the effect of restoring plasma ANG II levels on the activities of these enzymes. The studies proposed in this application could open an entirely new area in the understanding of the physiological roles of ANG II, namely the maintenance of normal vascular relaxation by preventing oxidative stress in resistance arteries.

Public Health Relevance

A growing body of evidence indicates that elevated dietary salt intake leads to dramatic alterations in vascular function without an increase in blood pressure. Many of the vascular changes occurring in rats and other species fed high salt diet are reminiscent of pathological alterations seen in vascular diseases such as hypertension, atherosclerosis, and hypercholesterolemia. Impaired vascular function with high salt diet appears to be mediated by increased oxidative stress in the blood vessels and suppression of the hormone angiotensin II (ANG II). This project will test the hypothesis that ANG II suppression leads directly to increased oxidative stress via down-regulation of antioxidant defense mechanisms in the blood vessels. These studies should provide valuable insight into the early changes occurring in response to high salt diet prior to elevation of blood pressure in salt sensitive hypertension, as well as the pathological changes that occur in response to elevated dietary salt intake.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065289-12
Application #
8243526
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2000-09-20
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$376,200
Indirect Cost
$128,700
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Raffai, Gábor; Lombard, Julian H (2016) Angiotensin-(1-7) Selectively Induces Relaxation and Modulates Endothelium-Dependent Dilation in Mesenteric Arteries of Salt-Fed Rats. J Vasc Res 53:105-118
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
Frisbee, Jefferson C; Butcher, Joshua T; Frisbee, Stephanie J et al. (2016) Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol 310:H488-504
Priestley, Jessica R C; Kautenburg, Katie E; Casati, Marc C et al. (2016) The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. Am J Physiol Heart Circ Physiol 310:H478-87
Beyer, Andreas M; Fredrich, Katherine; Lombard, Julian H (2014) Response to ""Does angiotensin-dependent superoxide production help to prevent salt-induced endothelial dysfunction in 2 kidney-1 clip hypertensive rats?"". Am J Hypertens 27:640
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
Pavlov, Tengis S; Levchenko, Vladislav; O'Connor, Paul M et al. (2013) Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol 24:1053-62
Beyer, Andreas M; Fredrich, Katherine; Lombard, Julian H (2013) AT1 receptors prevent salt-induced vascular dysfunction in isolated middle cerebral arteries of 2 kidney-1 clip hypertensive rats. Am J Hypertens 26:1398-404

Showing the most recent 10 out of 59 publications