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REVIEW
HIGHLIGHTED TOPIC
Physiology of the Aging Vasculature
1Cardiovascular Research, Institute of Physiology, and Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; 2Department of Cardiology, Cardiovascular Center, University Hospital, Zurich, Switzerland; and 3Division of Cardiology, Second Faculty of Medicine, University "La Sapienza" Ospedale Sant'Andrea, Rome, Italy
Submitted 28 April 2008 ; accepted in final form 27 August 2008
ABSTRACT
Accumulation of oxidative stress with age is hypothesized to be the primary causative mediator of age-associated diseases. Among different tissues, aging vessels are known to accumulate oxidative damage and undergo functional impairment. Oxidative stress affects the availability and/or balance of key regulators of vascular homeostasis and favors the development of cardiovascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial enzyme p66Shc is an adaptor protein and plays an important role as a redox enzyme implicated in mitochondrial eactive oxygen species generation and translation of oxidative signals into apoptosis. Mice lacking p66Shc–/– gene display reduced production of intracellular oxidants and a 30% prolonged life span. For this reasons, a series of studies conceived to elucidate the function of p66Shc and its possible implication in age-associated cardiovascular diseases have been carried out. Indeed, p66Shc–/– mice have been shown to be protected from age-dependent endothelial dysfunction as well as age-related risk factors such as diabetes and hypercholesterolemia. This review focuses on delineating the role of the p66Shc adaptor protein and its potential implication in the pathophysiology of aging and age-related cardiovascular disease.
cardiovascular disease; reactive oxygen species
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ROS are principally generated in mitochondria partly as a result of aerobic respiration, and in this context the mitochondrial adaptor protein p66Shc represents an interesting focus. In fact, genetic ablation of p66Shc in the mouse was shown to reduce production of intracellular oxidants and consequently prolong life span by 30% (26). The mammalian Shc locus encodes for three different adaptor proteins with respective molecular masses of 46, 52, and 66 kDa. The three isoforms share a Src-homology 2 domain, a collagen-homology region, and a phosphotyrosine-binding domain. However, the splice variant p66Shc, which contains a unique NH2-terminal region, is the only isoform to play an important role as a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals into apoptosis (5). p66Shc has been proposed to regulate ROS production by controlling the partition of ATP generation in the cell and by participating to the electron flow chain in the mitochondria (30). In fact in the absence of p66shc, mitochondrial oxidative phosphorylation is reduced in favor of glycolysis. Because mitochondrial electron flow, besides being the major source of ATP, also represents the major producer of cellular ROS, this may provide an explanation for the decreased production of ROS observed in p66Shc–/– cells and organisms (30). In light of its pivotal role in ROS generation, many efforts have been made to investigate the biochemical and pathophysiological role of p66Shc in age-dependent, ROS-mediated cardiovascular disease. Indeed, because age is considered an independent risk factor (16, 28), the identification of a novel mediator of age-associated changes in cardiovascular function could set basis for the development of therapeutical strategies to reduce aging-dependent cardiovascular disease.
P66SHC: ROLE IN AGING AND AGE-RELATED DISEASE
Aging vessels exhibit an increased production of ROS and in turn undergo functional impairment as a result of the decrease in NO bioavailability (2, 8, 11, 35, 37). Indeed, aged vessels generate an excess of O2– which rapidly inactivates NO, leading to the formation of the oxidant ONOO– (3, 33). ONOO–, among other ROS, penetrates across cellular membranes and inactivates, by nitration, several proteins, including free radical scavengers (36, 40). The identification of molecular pathways modulating the endothelial cell's redox state is therefore relevant for our understanding of mechanisms linking endothelial dysfunction and atherosclerosis in aging. In view of its role in determining the redox state of cells and their responses to free radicals (26), p66Shc adaptor protein has been regarded as a key player involved in mediating age-dependent loss of endothelial integrity. In line with this hypothesis, p66Shc–/– mice were shown to be protected from age-dependent endothelial dysfunction (13). Wild-type mice display age-dependent loss of acetylcholine-induced, NO-mediated vasorelaxation, whereas p66Shc–/– mice do not (13). In line with this, aged p66Shc–/– mice, unlike age-matched wild types, show increased endothelial bioavailability of NO, lower aortic O2– levels, and reduced aortic 3-nitrotyrosine content (13), thus suggesting a potential mechanism by which NO availability and vasorelaxant responses are preserved in aged p66Shc–/– mice. Based on these findings, one could also speculate that this is one of the mechanisms involved in the extended life span observed in p66Shc–/– mice.
Age-dependent endothelial dysfunction is not only explained by a steady loss of NO bioavailability caused by increased scavenging. Indeed, the vasculature is exposed to ROS damage, leading to endothelial cells death throughout its lifetime. In normal conditions, however, a balance between ROS damage and endothelial progenitor cells (EPC)-mediated repair exists (9) and guarantees endothelial integrity. This balance becomes disturbed with age due to an increased production of ROS, which in turn causes more damage and a decreased EPC's function, eventually leading to organ dysfunction (1). In keeping with the theory of an enhanced age-dependent ROS production, aged mice display enhanced endothelial mitochondrial ROS compared with young mice. The increased ROS production observed in aged mice could be the explanation for 1) the decreased endothelial cells function and 2) the decreased EPC-mediated repair, ultimately leading to vascular dysfunction. This changes, however, are not observed in age-matched p66Shc–/– mice, which present lower levels of ROS and a preserved endothelial function (13).
The possible role of p66Shc in the aging process of humans was recently investigated (32). Both p66Shc protein and messenger RNA were assessed in young people, elderly, and centenarians. Paradoxically, in this study, the expression of p66Shc was shown to increase with age (32), thus creating an apparent controversy with respect to the findings previously observed in mice (26). Although similar Shc genomic organization, transcript assembly as well as a high degree of amino acid identity have been observed in mice and in humans (27), this apparent contradiction in terms deserves more scientific efforts to be fully comprehended. For instance, it would be interesting to investigate whether human p66Shc protein remains functional in aging or perhaps undergoes an adaptive response to age-dependent cellular damage in vascular tissue. In any case, this observation does not preclude that p66Shc indeed mediates aging also in humans.
The initial theory that p66Shc may be at the crossroad between ROS production and arterial dysfunction drove one of the earliest investigations meant for elucidating its role in arterial atherogenesis (29). Wild-type and p66Shc–/– mice were fed a normocholesterolemic diet or a high-fat diet and then systemic vs. vascular levels of oxidative stress, as well as the extent of atherogenesis, were investigated. In this experimental setting, the authors found that wild-type mice fed a high fat diet showed much enhanced early aortic lesion formation compared with p66Shc–/–. This finding was recorded despite the fact that the lipid profile was unchanged in the two strains. In addition, p66Shc–/– mice exhibited a decrease in intimal foam cells formation, arterial oxidized LDLs as well as systemic plasma isoprostanes (29).
A later report once again proposed a correlation between plasma levels of LDL cholesterol, early markers of arterial dysfunction and p66Shc in pacemaker-implanted patients (6) thus confirming that p66Shc plays a role in translating the effects of different age-related risk factors into arterial dysfunction and early atherosclerotic lesions.
Abnormal glucose metabolism predominantly affects older individuals; indeed, 35% of the aged population presents, to some degree, abnormal glucose tolerance and shows signs of insulin resistance (17, 18). Hyperglycemic states frequently encountered in such conditions are thought to play a central role in generation of ROS, leading to arterial endothelial dysfunction and later to atherosclerosis (34, 39). Indeed, high levels of glucose induce a cascade of cellular events that increase the production of free radicals, thus decreasing NO bioavailability and eventually leading to vascular dysfunction (10, 15). In conditions of raised glucose plasma levels, p66Shc is known to oxidize cytochrome c and in turn to generate proapoptotic ROS through a PKC-β-dependent pathway (7, 30). In line with this concept, peripheral blood monocytes from patients with diabetes mellitus were shown to have increased p66Shc mRNA expression compared with healthy subjects (31). The putative role of p66Shc in hyperglycemia-induced, ROS-mediated vascular dysfunction was investigated further by separate studies. An interesting study by Menini et al. (25) demonstrated that p66Shc–/– mice are protected against diabetic glomerulopathy, a leading cause of chronic renal failure (25). Indeed, p66Shc–/– mice did not show high glucose-induced, ROS-dependent increase in glomerular cell apoptosis and extracellular matrix deposition, thus underlining once more the pivotal role of p66Shc in translating ROS-related insults into apoptosis.
The role of p66Shc in mediating hyperglycemia-induced, ROS-dependent endothelial dysfunction was recently addressed in a mouse model of Type 1 diabetes (7). In this study, p66Shc–/– hyperglycaemic mice, unlike wild types, were shown to be protected from endothelial dysfunction by means of an unaltered ROS production, which resulted in a preserved NO bioavailability (7). Interestingly, p66Shc protein expression was increased in aortas from wild-type hyperglycemic mice compared with normoglycemic controls, thus underlining a causal relationship between high glucose, ROS, p66Shc, and vascular dysfunction (7).
FUTURE RESEARCH DIRECTIONS
Epidemiological studies demonstrated that even in the absence of other risk factors such as diabetes or high cholesterol, aging per se increases cardiovascular morbidity and mortality. A better understanding of the molecular mechanisms of aging and its interaction with risk factors could, in the future, lead to the development of therapeutical interventions aimed at decreasing the functional decline of the cardiovascular system.
From an evolutionary perspective, ROS pathways have developed for enhancing energy metabolism and host defense. However, in the modern world (i.e., fewer infections, high caloric intake), the accumulation of ROS observed in aging appears to be heavily implicated in age-associated cardiovascular diseases. Thus redox-sensitive molecular pathways such as p66Shc are under intensive investigation as the common denominators of the pathophysiology of several cardiovascular risk factors. In this view, the concept that p66Shc regulates ROS production, thereby determining cellular and organ decline raises the question whether pharmacological modulation of its expression and/or activity may be effective in delaying the onset of age-dependent vascular disease. Thus research efforts should persist in the current direction to fully elucidate the exact relationship between all the factors (namely ROS, aging, risk factors and redox pathways). that cause the unrelenting decline in efficiency of the cardiovascular system.
GRANTS
This work was supported by the Swiss National Research Foundation (Grant no. 3100068118.02 to T. F. Lüscher), the Swiss Heart Foundation (to G. G. Camici), and MERCATOR Foundation (to T. F. Lüscher).
FOOTNOTES
Address for reprint requests and other correspondence: T. F. Lüscher, Cardiology and Cardiovascular Center, Univ. Hospital, Ramistrasse, 100 CH-8091 Zürich, Switzerland (e-mail: karlue{at}usz.unizh.ch)
REFERENCES
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E. G. Lakatta Arterial aging is risky J Appl Physiol, October 1, 2008; 105(4): 1321 - 1322. [Full Text] [PDF]
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