Targeting Mitochondria in Age-Related Vascular Changes
A New Arrow to the Bow of Antioxidant Treatment?
See related article, pp 1056–1063
Aging is a powerful determinant of vascular changes, being associated with elastin degradation and accumulation of collagen fibers within the vascular wall, ultimately leading to increased arterial stiffness. The ability of arterial stiffness of predicting cardiovascular events and the availability of techniques that enable its simple measures makes this parameter one of the most utilized in cardiovascular research.1
Exposure to cardiovascular risk factors, including hypertension, smoking, or diabetes mellitus, can amplify and accelerate the vascular remodeling observed with aging, leading to a faster increase of arterial stiffness (a phenomenon known as early vascular aging).2 This is commonly preceded and accompanied by the development of endothelial dysfunction—the earliest manifestation of an altered vascular homeostasis.
In a quiescent state, endothelial cells have a key role in regulating the vascular tone and structure. When exposed to cardiovascular risk factors, the endothelium results in a switch in signaling from an NO-mediated silencing of cellular processes toward activation by redox signaling. The overproduction of reactive oxygen species (ROS) reduces NO availability and activates pathways that lead to early vascular remodeling.3
Various enzymatic and nonenzymatic sources of ROS have been identified within the arterial wall of patients with increased vascular stiffness, including nicotinamide adenine dinucleotide phosphate oxidase, cyclooxygenase, xanthine oxidase, and the endothelial NO synthase.3 Among these, mitochondria have recently drawn increasing attention because of their capacity to produce high levels of ROS (mtROS) even under physiological conditions. mtROS is generated at complex I and complex III in the mitochondrial electron transport chain and although historically considered a toxic by-product of mitochondrial metabolism, it is now documented that it can act as a signaling molecule.4 The contribution of mtROS to the global levels of ROS within endothelial cells might be particularly important in some conditions, including obesity and diabetes mellitus, as well as in physiological aging. In such circumstances, several pathological stressors may induce an excess of mtROS generation, which in turn may reduce NO availability and generate inflammatory cytokines, thus favoring the vascular atherosclerosis (Figure).4 In aging, instead, a defective mitophagy (the mechanisms used by cells to eliminate damaged mitochondria) leads to accumulation of dysfunctional mitochondria that produce a larger amount of mtROS.5 Thus, targeting mtROS might represent an effective strategy to prevent the endothelial dysfunction and arterial stiffening observed in advanced age. In humans, administration of MitoQ (a potent mitochondria-targeted antioxidant) reverses age-related vascular dysfunction detected in skeletal muscle feed arteries biopsied from older adults.6
In this issue of Hypertension, Rossman et al7 investigated in a randomized, placebo-controlled, double-blind crossover design study, the impact of oral supplementation with MitoQ on brachial artery endothelial function and vascular stiffness in a small group of healthy middle aged/old adults. The novel finding of this elegant study is the demonstration that in only 6 weeks of treatment, the group treated with MitoQ showed a significant improvement in endothelial function and reduction in aortic stiffness. These effects were accompanied by a significant reduction of plasma oxidized low-density lipoprotein—a circulating marker of oxidative stress. This study extends the authors’ previous preclinical finding documenting restoration of endothelial-dependent vasodilation in old mice fed with oral supplementation of MitoQ.8
The rigorous study design provides strong support to the hypothesis that mtROS might be in the causal pathway for endothelial dysfunction and, more generally, cardiovascular disease. The use of the most reliable techniques for the assessment of vascular changes in humans adds solidity to the findings. The flow-mediated dilation has been previously used in large clinical trials, and its strong relationship with cardiovascular prognosis has been documented in numerous population-based follow-up studies.9 Similarly, carotid-to-femoral pulse wave velocity represents the most validated and gold standard technique for the assessment of aortic stiffness, accepted by the European Society of Hypertension as a marker of asymptomatic organ damage to use in clinical research.
Although this report represents the first randomized clinical trial in humans to demonstrate a protective effect of MitoQ toward vascular aging, it has some limitations and leaves unaddressed questions, which deserve further comments.
One possible limitation of this clinical trial lies in the characteristics of the patients included in the study. Although the authors aimed to include a population that was free of overt cardiovascular risk factors, smoking history and renal function have not been assessed. Also, because of the stringent inclusion criteria, the subjects recruited to the study correspond to a small proportion of individuals in the general population, where aging is commonly associated to exposure to cardiovascular risk factors and development of several age-related diseases. The lack of patients with established cardiovascular disease does not enable understanding whether MitoQ could represent an effective treatment also in people with advanced vascular damage, where modulation of mtROS might be less effective in preventing cardiovascular complications.
Another minor concern is the lack of specific measures of mtROS in the vascular wall and blood cells of patients treated with MitoQ. This makes it impossible to understand whether the effects of the drug on endothelial function and arterial stiffness are related to reduced production of mtROS only or are because of other off-target effects.
The oral supplementation of MitoQ induced a significant increase in its circulating levels. This is important because mtROS is not only involved in vascular damage but is also increased in the myocardium of patients with heart failure and coronary artery disease. Although this suggests that MitoQ could represent an effective treatment also in patients with primary heart disease, the lack of information on cardiac function/structure in the present study does not enable extrapolation of the results to other clinical settings.
The findings by Rossman et al7 should be interpreted in the context of the considerable number of studies that already attempted antioxidant treatments in cardiovascular disease, of which MitoQ is the latest chapter. The rationale for using antioxidants to prevent cardiovascular disease is provided by several reports documenting an increased amount of vascular oxidative stress in subjects exposed to cardiovascular risk factors. However, results of randomized clinical trials using antioxidant molecules to prevent cardiovascular hard end points have been disappointing.10 MitoQ is a potent mtROS scavenger, thus specifically interrupting a direct trigger of proinflammatory cytokine production. Accordingly, such peculiar mechanism of action allows us to hypothesize that MitoQ might be a new arrow to our bow to fight the atherosclerotic process—a recognized chronic inflammatory disease.
Given its potential spectrum of biological activities, it is evident that the discovery of MitoQ is opening up many new research perspectives. The present article by Rossman et al7 substantially enriches our understanding of the crucial role played by mitochondria in regulating vascular homeostasis. Further studies, including also population at high risk of cardiovascular disease (such as diabetes mellitus), are necessary to confirm the potential role of mtROS as a novel target for cardiovascular disease prevention.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
- © 2018 American Heart Association, Inc.
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