Role of oxidative and nitrosative stress, longevity genes and poly(ADP-ribose) polymerase in cardiovascular dysfunction associated with aging

Abstract

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity. Although aging is inevitable, cardiovascular gerontologists recognize that a better understanding of the aging process in the not-so-distant future will lead to pharmacological interventions that considerably delay the functional decline of the cardiovascular system. Since the original publishing of the free radical theory of aging, an increased production of reactive oxygen species has been implicated both in the aging process and the development of age-related cardiovascular diseases. This review focuses on the role of oxidative and nitrosative stress in cardiovascular dysfunction in aging, downstream mechanisms including activation of NF- kappaB, and the role of poly(ADP-ribose)polymerase (PARP) and longevity genes that are linked to regulation of cellular redox status and oxidative stress resistance (p66(shc), sirtuins, FOXO transcription factors).

Fig 1

(A). Aging-induced endothelial dysfunction, represented as changes in endothelium-dependent responses (vascular relaxation, dilation or NO release) of vessels from various vascular beds (aorta, coronary, carotid, femoral or mesentery artery), induced by sub-maximal dose of a vasodilator (acetylcholine and the calcium ionophore A23187). This figure has been compiled from both published [, , , , –81] and unpublished data. Age is shown as percentage of maximal lifespan of each species. (B). Aging-induced decline in cardiac performance in F344 rats (representative pressure-volume loops, pressure signals and dP/dt (C) obtained with the Millar P-V conductance catheter system).

Fig 2

A set of representative 2DE separation of proteins from the carotid artery of 3 month old (young) and 26 month old (aged) F344 rats illustrating age-related changes in the vascular proteome. Arteries were homogenized and the proteins were extracted as described [3]. Samples were focused on 7 cm pH 3-10 NL IEF strips and separated on 12% second-dimension gels. Future studies should characterize both aging-induced gene expression changes at the protein level and post-translational protein modifications related to an increased oxidative-nitrosative stress present in the aged vasculature.

Fig 3

(A). Increased number of passages are associated with a decreased mRNA expression of forkhead transcription factors Foxo1 and Foxo4 in rat coronary arterial endothelial cells (CAEC). Real-time PCR measurements were performed as reported [3, 15]. mVISTA plots showing the percent of conservation between the mouse and human at the 5' flanking region (3000 bp) of the catalase (B) and Mn-SOD genes (C). The arrows point to the location of conserved putative Foxo binding sites.

Fig 4

(A). Representative Western blot showing PARP-1 content in coronary arteries of young (3 month old) and aged (27 month old) F344 rats. Note that an increased amount of 89-kDa cleaved fragment of PARP-1 was present in the aged vessels, which likely corresponds to an enhanced endothelial apoptosis in these arteries. It is important to point out that PARP-1 expression does not necessarily correlate with PARP activity. (B). 3D structure of PARP-1 with the evolutionary conserved catalytic subunit (red) (based on the results of automated comparative analysis at Entrez’s Molecular Modeling Database, which is available at: http://www.ncbi.nlm.nih.gov/Entrez/structure.html). Asterisk shows the putative binding site of PARP inhibitors. Purple: regulatory subunit. C: The PARP inhibitor PJ34 improves endothelial function in the aorta of aged rats (redrawn from data presented in ref [62]).

Fig 5

Proposed scheme for the role of oxidative and nitrosative stress, longevity genes and poly(ADP-ribose) polymerase in cardiovascular dysfunction associated with aging.