Redox Signaling in Hypertension

Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Ontario, Canada.
Cardiovascular Research (Impact Factor: 5.94). 08/2006; 71(2):247-58. DOI: 10.1016/j.cardiores.2006.05.001
Source: PubMed


Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca(2+) concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with hypertension.

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    • "activity is an important factor for the maintenance of the peripheral sympathetic tone and BP control in health and disease [4] [5] [6]. The oxidative stress is the result of excessive generation of oxidizing agents, and the inadequate removal of ROS and consequent imbalance between the antioxidant and the prooxidant mechanisms were shown to be involved in the pathogenesis of hypertension [7] [8] [9]. Any molecule presenting oxygen with a high oxidative capacity is considered as potential ROS, as for instance the superoxide ion (O 2 À ), the hydroxyl radical (OH À ), and the hydrogen peroxide (H 2 O 2 ). "
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    ABSTRACT: Bradykinin-potentiating peptides (BPPs) from the South American pit viper snake venom were the first natural inhibitors of the human angiotensin I-converting enzyme (ACE) described. The pioneer characterization of the BPPs precursor from the snake venom glands by our group showed for the first time the presence of the C-type natriuretic peptide (CNP) in this same viper precursor protein. The confirmation of the BPP/CNP expression in snake brain regions correlated with neuroendocrine functions stimulated us to pursue the physiological correlates of these vasoactive peptides in mammals. Notably, several snake toxins were shown to have endogenous physiological correlates in mammals. In the present work, we expressed in bacteria the BPPs domain of the snake venom gland precursor protein, and this purified recombinant protein was used to raise specific polyclonal anti-BPPs antibodies. The correspondent single protein band immune-recognized in adult rat brain cytosol was isolated by 2D-SDS/PAGE and/or HPLC, before characterization by MS fingerprint analysis, which identified this protein as superoxide dismutase (SOD, EC, a classically known enzyme with antioxidant activity and important roles in the blood pressure modulation. In silico analysis showed the exposition of the BPP-like peptide sequences on the surface of the 3D structure of rat SOD. These peptides were chemically synthesized to show the BPP-like biological activities in ex vivo and in vivo pharmacological bioassays. Taken together, our data suggest that SOD protein have the potential to be a source for putative BPP-like bioactive peptides, which once released may contribute to the blood pressure control in mammals. Copyright © 2015 Elsevier Inc. All rights reserved.
    Biochemical pharmacology 06/2015; 96(3). DOI:10.1016/j.bcp.2015.05.012 · 5.01 Impact Factor
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    • "It has been suggested that partially replacing dietary carbohydrate with protein may also help in the prevention and treatment of hypertension (Rebholz et al., 2012). The pathophysiology of hypertension is complex, although the crucial roles of renin– angiotensin system (RAS), oxidative stress, and vascular inflammation in the development and the persistence of hypertension have been determined (Oparil & Haber, 1974; Paravicini & Touyz, 2006; Rahman, Gilmour, Jimenez, & MacNee, 2002; Salvemini, Ischiropoulos, & Cuzzocrea, 2003; Stauffer, Westby, & DeSouza, 2008). Bioactive peptides from food protein hydrolysis have been known to exhibit antioxidant, antiinflammatory , and antithrombotic activities along with ACE inhibitory effects (Balti et al., 2012; Fujita, Sasaki, & Yoshikawa, 1995; Ichimura et al, 2009; Miguel & Aleixandre, 2006). "
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    ABSTRACT: Two angiotensin converting enzyme (ACE) inhibitory tripeptides, IQW and LKP, were previously characterized from egg white protein ovotransferrin. ACE is a key enzyme of the renin–angiotensin system (RAS) which generates angiotensin II (Ang II) from its precursor and increases blood pressure (BP) in the body. This study tested the blood pressure lowering potential of orally administered IQW and LKP in spontaneously hypertensive rats. IQW and LKP treatment decreased mean blood pressure (MAP) by ~19 and ~30 mmHg, respectively, compared to untreated SHRs. The change in BP was accompanied by the preservation of nitric oxide dependent vasorelaxation and lowering of plasma Ang II levels. Furthermore IQW, but not LKP, also reduced intercellular adhesion molecule-1 (ICAM-1) expression and nitrotyrosine levels in arteries, suggesting additional protective effects against inflammation and oxidative/nitrosative stress. These results demonstrate anti-hypertensive effects of IQW and LKP in vivo and a reduction of circulating Ang II levels, with additional anti-inflammatory and antioxidant effects mediated by IQW.
    Journal of Functional Foods 03/2015; 13. DOI:10.1016/j.jff.2014.12.028 · 3.57 Impact Factor
    • "This effect was mediated by the activation of both NADPH and nicotinamide adenine dinucleotide oxidases [67] [68], through the obligatory action of p22 phox [68]. These findings were demonstrated to be mediated through AT1R and confirmed in rat studies, in which Ang II-induced hypertension determined an increase in Nox-derived O 2 À of vascular origin and endothelial dysfunction, effects blunted by the AT1R blocker losartan [69] [70]. Ang II is functionally associated with Nox1, Nox2, and Nox5 and variably with Nox4 in the vasculature and, as shown by in vitro studies, is a potent stimulator of Nox's [71]. "
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    ABSTRACT: Reactive oxygen species (ROS) are intermediates in reduction-oxidation reactions that begin with the addition of one electron to molecular oxygen, generating the primary ROS superoxide, which in turn interacts with other molecules to produce secondary ROS, such as hydrogen peroxide, hydroxyl radical, and peroxynitrite. ROS are continuously produced during metabolic processes and are deemed to play an important role in cardiovascular diseases, namely, myocardial hypertrophy and fibrosis, atherosclerosis, via oxidative damage of lipids, proteins, and deoxyribonucleic acid.
    Free Radical Biology and Medicine 03/2015; 88. DOI:10.1016/j.freeradbiomed.2015.02.037 · 5.74 Impact Factor
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