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      Molecular Targets of Antihypertensive Peptides: Understanding the Mechanisms of Action Based on the Pathophysiology of Hypertension

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          Abstract

          There is growing interest in using functional foods or nutraceuticals for the prevention and treatment of hypertension or high blood pressure. Although numerous preventive and therapeutic pharmacological interventions are available on the market, unfortunately, many patients still suffer from poorly controlled hypertension. Furthermore, most pharmacological drugs, such as inhibitors of angiotensin-I converting enzyme (ACE), are often associated with significant adverse effects. Many bioactive food compounds have been characterized over the past decades that may contribute to the management of hypertension; for example, bioactive peptides derived from various food proteins with antihypertensive properties have gained a great deal of attention. Some of these peptides have exhibited potent in vivo antihypertensive activity in both animal models and human clinical trials. This review provides an overview about the complex pathophysiology of hypertension and demonstrates the potential roles of food derived bioactive peptides as viable interventions targeting specific pathways involved in this disease process. This review offers a comprehensive guide for understanding and utilizing the molecular mechanisms of antihypertensive actions of food protein derived peptides.

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          Most cited references153

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          Blood pressure and end-stage renal disease in men.

          End-stage renal disease in the United States creates a large burden for both individuals and society as a whole. Efforts to prevent the condition require an understanding of modifiable risk factors. We assessed the development of end-stage renal disease through 1990 in 332,544 men, 35 to 57 years of age, who were screened between 1973 and 1975 for entry into the Multiple Risk Factor Intervention Trial (MRFIT). We used data from the national registry for treated end-stage renal disease of the Health Care Financing Administration and from records on death from renal disease from the National Death Index and the Social Security Administration. During an average of 16 years of follow-up, 814 subjects either died of end-stage renal disease or were treated for that condition (15.6 cases per 100,000 person-years of observation). A strong, graded relation between both systolic and diastolic blood pressure and end-stage renal disease was identified, independent of associations between the disease and age, race, income, use of medication for diabetes mellitus, history of myocardial infarction, serum cholesterol concentration, and cigarette smoking. As compared with men with an optimal level of blood pressure (systolic pressure or = 210 mm Hg or diastolic pressure > or = 120 mm Hg) was 22.1 (P < 0.001). These relations were not due to end-stage renal disease that occurred soon after screening and, in the 12,866 screened men who entered the MRFIT study, were not changed by taking into account the base-line serum creatinine concentration and urinary protein excretion. The estimated risk of end-stage renal disease associated with elevations of systolic pressure was greater than that linked with elevations of diastolic pressure when both variables were considered together. Elevations of blood pressure are a strong independent risk factor for end-stage renal disease; interventions to prevent the disease need to emphasize the prevention and control of both high-normal and high blood pressure.
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            Role of TNF-α in vascular dysfunction

            Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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              Oxidative stress and endothelial dysfunction in hypertension.

              Systemic arterial hypertension is a highly prevalent cardiovascular risk factor that causes significant morbidity and mortality, and is becoming an increasingly common health problem because of the increasing longevity and prevalence of predisposing factors such as sedentary lifestyle, obesity and nutritional habits. Further complicating the impact of this disease, mild and moderate hypertension are usually asymptomatic, and their presence (and the subsequent increase in cardiovascular risk) is often unrecognized. The pathophysiology of hypertension involves a complex interaction of multiple vascular effectors including the activation of the sympathetic nervous system, of the renin-angiotensin-aldosterone system and of the inflammatory mediators. Subsequent vasoconstriction and inflammation ensue, leading to vessel wall remodeling and, finally, to the formation of atherosclerotic lesions as the hallmark of advanced disease. Oxidative stress and endothelial dysfunction are consistently observed in hypertensive subjects, but emerging evidence suggests that they also have a causal role in the molecular processes leading to hypertension. Reactive oxygen species (ROS) may directly alter vascular function or cause changes in vascular tone by several mechanisms including altered nitric oxide (NO) bioavailability or signaling. ROS-producing enzymes involved in the increased vascular oxidative stress observed during hypertension include the NADPH oxidase, xanthine oxidase, the mitochondrial respiratory chain and an uncoupled endothelial NO synthase. In the current review, we will summarize our current understanding of the molecular mechanisms in the development of hypertension with an emphasis on oxidative stress and endothelial dysfunction.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                24 December 2014
                January 2015
                : 16
                : 1
                : 256-283
                Affiliations
                [1 ]Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB T6G 2P5, Canada; E-Mail: kaustav@ 123456ualberta.ca
                [2 ]Cardiovascular Research Centre, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: jianping.wu@ 123456ualberta.ca ; Tel.: +1-780-492-6885; Fax: +1-780-492-4265.
                Article
                ijms-16-00256
                10.3390/ijms16010256
                4307246
                25547491
                eab37f24-30e3-4492-a47a-55574355200f
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 September 2014
                : 15 December 2014
                Categories
                Review

                Molecular biology
                antihypertensive peptides,spontaneously hypertensive rats,hypertension,angiotensin converting enzyme,endothelin,nitric oxide

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