Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria?

被引:120
作者
de Cavanagh, Elena M. V. [2 ]
Inserra, Felipe [3 ,4 ]
Ferder, Leon [1 ]
机构
[1] Ponce Sch Med, Dept Physiol & Pharmacol, Ponce, PR 00732 USA
[2] Austral Univ Hosp, Dept Cardiol, Ctr Hypertens, Derqui, Argentina
[3] Univ Buenos Aires, Sch Med, Inst Cardiovasc Pathophysiol, Buenos Aires, DF, Argentina
[4] Fresenius Med Care Argentina, Buenos Aires, DF, Argentina
关键词
Renin-angiotensin system; ACE inhibitor; Angiotensin blockers; PPARs; Calorie restriction; CONVERTING ENZYME-INHIBITION; PROLIFERATOR-ACTIVATED RECEPTORS; PROTEIN OXIDATIVE DAMAGE; SPONTANEOUSLY HYPERTENSIVE-RATS; TERM CALORIC RESTRICTION; FREE-RADICAL GENERATION; CYTOCHROME-C RELEASE; SMOOTH-MUSCLE-CELLS; GROWTH-FACTOR-I; MESSENGER-RNA;
D O I
10.1093/cvr/cvq285
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Protein and lipid oxidation-mainly by mitochondrial reactive oxygen species (mtROS)-was proposed as a crucial determinant of health and lifespan. Angiotensin II (Ang II) enhances ROS production by activating NAD(P) H oxidase and uncoupling endothelial nitric oxide synthase (NOS). Ang II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS blockade) increases survival and prevents age-associated changes. RAS blockade reduces mtROS and enhances mitochondrial content and function. This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction. Since Ang II is a pleiotropic peptide, the age-protecting effects of RAS blockade are expected to involve a variety of other mechanisms. Caloric restriction (CR)-an age-retarding intervention in humans and animals-and RAS blockade display a number of converging effects, i.e. they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and insulin-like growth factor-1; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H2O2 production; and increase uncoupling protein-2 and sirtuin expression. Anumber of these overlapping effects involve changes in mitochondrial function. In CR, peroxisome proliferator-activated receptors (PPARs) seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition up-regulates PPARs; therefore, it is feasible that PPAR modulation is pivotal for mitochondrial protection by RAS blockade during rodent ageing. Other potential mechanisms that may underlie RAS blockade's mitochondrial benefits are TGF-beta down-regulation and up-regulation of Klotho and sirtuins. In conclusion, the available data suggest that RAS blockade deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.
引用
收藏
页码:31 / 40
页数:10
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