Cardiovascular determinants of life span

Abstract

The prevalence of cardiovascular diseases rises with aging and is one of the main causes of mortality in western countries. In view of the progressively aging population, there is an urge for a better understanding of age-associated cardiovascular diseases and its underlying molecular mechanisms. The risk factors for cardiovascular diseases include unhealthy diet, diabetes, obesity, smoking, alcohol consumption, physical inactivity, and aging. Increased production of oxygen-derived free radicals plays an important role in mediating cardiovascular diseases. Oxidative stress affects the availability and/or balance of key-regulators of vascular homeostasis and favors the development of cardiovascular diseases. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66Shc and the deacetylase enzyme SIRT1 were shown to be involved in different aspects of cardiovascular diseases. This review focuses on the latest scientific advances in understanding cardiovascular diseases associated to aging, as well as delineating the possible therapeutic implications of p66Shc and SIRT 1 in this process. AbstractThe prevalence of cardiovascular diseases rises with aging and it is one of the main causes of mortality in western countries. Thus there is an urge for a better understanding of cardiovascular diseases and underlying molecular mechanisms. The risk factors for cardiovascular diseases include unhealthy diet, diabetes, obesity, smoking, alcohol consumption, physical inactivity and aging. Increased production of oxygen-derived free radicals plays an important role in mediating cardiovascular diseases. Oxidative stress affects the availability and/or balance of key-regulators of vascular homeostasis and favours the development of cardiovascular diseases. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria.The mitochondrial protein p66Shc and the deacetylase enzyme SIRT1 were shown to be involved in different aspects of cardiovascular diseases. This review focuses on the latest scientific advances in understanding cardiovascular diseases as well as delineating the possible therapeutic implications of p66Shc and SIRT 1 in this process.3

Adaptor Protein p66 Shc Mediates Hypertension-Associated, Cyclic Stretch–Dependent, Endothelial Damage

“…20,21 Genetic deletion of p66 Shc in mice was shown to improve endothelial function in different disease models. 15,16,18 In particular, p66 Shc mediates vascular dysfunction observed in angiotensin II-treated, hypertensive mice.…”

“…8,9 A balance between ROS production and degradation is essential to maintain physiological cellular processes and function, 21 and the perturbation of this redox balance, by an increased ROS production and a decreased antioxidant capacity, induces oxidative stress resulting in endothelial dysfunction, 21 a common denominator to many cardiovascular diseases, such as hypertension. 36,37 Previously, NADPH oxidase has been demonstrated to be a major source for pathological stretch-increased O 2 − generation.…”

SIRT1/eNOS Axis as a Potential Target against Vascular Senescence, Dysfunction and Atherosclerosis

“…According to the free-radical theory, reactive oxygen species (ROS) may be potential candidates responsible for vascular dysfunction and atherosclerosis 13) , and upon the production of high levels of ROS, the redox balance is disturbed and cells shift into a state of oxidative stress, which subsequently leads to endothelial dysfunction and senescence with shortening of telomeres 14) . Endothelial NO synthase (eNOS) activity is reduced in human senescent endothelial cells, accompanied by a reduction of nitric oxide (NO) production.…”

Oxidized Low-Density Lipoprotein Activates p66 Shc via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, Protein Kinase C-β, and c-Jun N-Terminal Kinase Kinase in Human Endothelial Cells

“…This could be accounted for by several factors: (1) antioxidant supplements are already found in high concentrations in normal human diet; (2) additional antioxidant treatment may depress endogenous antioxidant defense systems; and (3) intracellular ROS production sites may be sequestered in organelles (for instance, mitochondria), thus preventing dietary antioxidants from reaching their putative site of action. 5 Therefore, inhibition of endogenous oxidant pathways seems to be a more promising therapeutic strategy.…”