Abstract
Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction. Oxidative stress caused by overproduction of reactive oxygen species (ROS) and/or by reduced expression of antioxidant enzymes is a major contributor to the progression of vascular senescence, pathologic remodeling of the vascular wall, and disease. Both oxidative stress and inflammation promote the development of senescence, a process by which cells stop proliferating and become dysfunctional. This review focuses on the role of the mitochondria and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Nox1 and Nox4 in vascular senescence, and their contribution to the development of atherosclerosis. Recent findings are reviewed, supporting a critical role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α), the inflammatory gene nuclear factor κB (NF-κB), zinc, the zinc transporters (ZnTs) ZnT3 and ZnT10, and angiotensin II (Ang II) in mitochondrial function, and their role in telomere stability, which provides new mechanistic insights into a previously proposed unified theory of aging.
Highlights
Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction
We demonstrated that zinc- and angiotensin II (Ang II)-induced senescence is mediated by upregulation of Nox1 expression [46,70] and that Nox1 overexpression is sufficient to induce VSMC senescence [46]
It is possible that zinc interacting with cysteine and histidine residues in the E-loop may induce oxidative stress by changing the type of reactive oxygen species (ROS) produced by Nox4
Summary
A hallmark of mammalian aging, is a process in which cells stop proliferating and become dysfunctional, due to accumulation of mutations that cause damage to the DNA, proteins, and lipids. Senescent cells secrete an abnormal variety of molecules, including inflammatory cytokines, growth factors, ROS, and extracellular matrix components; these molecules modify the cellular microenvironment, creating a vicious cycle of oxidative stress and inflammation causing tissue dysfunction during aging. This process is known as the senescence associated secretory phenotype (SASP) [2,3]. Through the SASP, these senescent cells may pathologic vascular Another protective mechanism that becomes dysfunctional during aging is the autophagy [15,16], contribute to the spread of senescence in the adventitia and endothelium and recruitment of a catabolic process by which protein aggregates and dysfunctional organelles, like mitochondria, inflammatory cells. These pathways can be selectively activated in different tissues depending on the expression of ROS generating enzymes, such as NADPH oxidases, expression of growth factor and hormone receptors, and downstream signal transduction pathways
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