Contribution of mitochondrial oxidative stress to hypertension

Abstract

Purpose of review In 1954 Harman proposed the free radical theory of aging, and in 1972 he suggested that mitochondria are both the source and the victim of toxic free radicals. Interestingly, hypertension is age-associated disease and clinical data show that by age 70, 70% of the population has hypertension and this is accompanied by oxidative stress. Antioxidant therapy however is not currently available and common antioxidants like ascorbate and vitamin E are ineffective in preventing hypertension. The present review focuses on molecular mechanisms of mitochondrial oxidative stress and therapeutic potential of targeting mitochondria in hypertension. Recent findings In the past several years, we have shown that the mitochondria become dysfunctional in hypertension and have defined novel role of mitochondrial superoxide radicals in this disease. We have shown that genetic manipulation of mitochondrial antioxidant enzyme superoxide dismutase (SOD2) affects blood pressure and have developed mitochondria-targeted therapies such as SOD2 mimetics that effectively lower blood pressure. The specific mechanism of mitochondrial oxidative stress in hypertension, however, remains unclear. Recent animal and clinical studies have demonstrated several hormonal, metabolic, inflammatory, and environmental pathways contributing to mitochondrial dysfunction and oxidative stress. Summary Nutritional supplements, calorie restriction, and life style change are the most effective preventive strategies to improve mitochondrial function and reduce mitochondrial oxidative stress. Aging associated mitochondrial dysfunction, however, reduces efficacy of these strategies. Therefore, we propose that new classes of mitochondria-targeted antioxidants can provide high therapeutic potential to improve endothelial function and reduce hypertension.

Analysis of metabolic profiles of generalized aggressive periodontitis

“…This biosynthetic pathway is regulated by tyrosine hydroxylase, which is an enzyme positively controlled by mitochondrial activity . Excessive action of mitochondria constitutes an oxidative stress . In our study, the elevated level of noradrenaline found in patients with GAgP may be the result of biochemical abnormality of tyrosine metabolism; in conditions of high mitochondrial function, the activity of hydroxylase increases, resulting in an accumulation of noradrenaline.…”

Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension

“…43 All these metabolic conditions increase mitochondrial acetylation and risk of hypertension. 19, 44–48 We suggest that imbalance between mitochondrial acetylation and reduced Sirt3 activity as a potential mechanistic link between metabolic conditions and hypertension.…”

“…44 It is therefore interesting to speculate that SOD2 hyperacetylation can be used as an integrative marker of mitochondrial impairment which can be beneficial as a prognostic factor in hypertension. Indeed, our animal data show positive correlation of severity of hypertension with SOD2 acetylation (Figure 7).…”

Nuclear genetic regulation of human mitochondrial RNA modification

“…Second, the missense mutation in PNPT1 (rs782572) that is associated with methylation level of mt-RNR2 (position 2617), is in high LD with rs197548, which is associated with systolic and diastolic blood pressure (Ehret et al 2016). Mitochondria have previously been linked to increased blood pressure, predominantly through mechanisms involving mitochondrial oxidative stress, however the exact mechanisms by which this is the case remain unclear (Dikalov and Dikalova 2016). We have previously observed associations between nuclear genetic variants influencing the expression of certain mitochondrial genes, mediated through the expression of PNPT1 (Ali et al 2019), and the identification of the overlap here suggests that RNA methylation level may also be playing a contributory role in the process.…”