Role of mitochondrial oxidative stress in hypertension

Abstract

Based on mosaic theory, hypertension is a multifactorial disorder that develops because of genetic, environmental, anatomical, adaptive neural, endocrine, humoral, and hemodynamic factors. It has been recently proposed that oxidative stress may contribute to all of these factors and production of reactive oxygen species (ROS) play an important role in the development of hypertension. Previous studies focusing on the role of vascular NADPH oxidases provided strong support of this concept. Although mitochondria represent one of the most significant sources of cellular ROS generation, the regulation of mitochondrial ROS generation in the cardiovascular system and its pathophysiological role in hypertension are much less understood. In this review, the role of mitochondrial oxidative stress in the pathophysiology of hypertension and cross talk between angiotensin II signaling, pathways involved in mechanotransduction, NADPH oxidases, and mitochondria-derived ROS are considered. The possible benefits of therapeutic strategies that have the potential to attenuate mitochondrial oxidative stress for the prevention/treatment of hypertension are also discussed.

Keywords: antioxidant; hypertension; mitochondria; oxidative stress; superoxide.

Fig. 1.

The central role of reactive oxygen species (ROS) in the mosaic theory of hypertension (59). The octagon indicates a closed system in equilibrium with the interdigitating regulatory mechanisms on each focal point. Note that ROS production contributes to each component of the mosaic theory.

Fig. 2.

Proposed conceptual model showing that development of hypertension and hypertension-related vascular alterations are associated with increases in vascular oxidative stress. The model predicts that the link between vascular oxidative stress and hypertension is bidirectional: oxidative stress both promotes the development of hypertension and contributes to hypertension-induced pathologies (including atherosclerosis, kidney failure, stroke, aorta aneurysms, vascular cognitive impairment). This emerging new concept is supported by both animal studies and clinical observations (24, 37, 66, 76, 78, 92, 95, 108, 113, 117).

Fig. 3.

Possible sites of ROS production in mitochondria, which can contribute to cellular oxidative stress in the cardiovascular system in hypertension. O₂^·−, superoxide; Cyt c, cytochrome c; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide; Q^·, ubiquinone; QH₂, ubiquinone; Ψ⁺, membrane potential.

Fig. 4.

Proposed role of redox-dependent cross talk between mitochondria and NADPH oxidases (NOXs) in vascular dysfunction in hypertension. CVD, cardiovascular disease; NO, nitirc oxide; ONOO⁻, peroxynitrite; eNOS, endothelial NO synthase; GPx, glutathione peroxidase; Trx₂, thioredoxin 2; mCat, catalase targeted to mitochondria; mK_ATP, ATP-sensitive K⁺ channel; ΔΨ_m, mitochondrial transmembrane potential.

Fig. 5.

Pressure-induced increases in mitochondrial ROS production in isolated, cannulated branches of the mouse middle cerebral artery. Data are relative changes in the buildup of MitoSox fluorescence intensities induced by stepwise increase in intraluminal pressure. Note that high pressure upregulates vascular mitochondrial ROS generation. MitoSox loading was performed as previously reported (26). Data are means ± SE (n = 6 in each group). *P < 0.01.