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Reactive oxygen species (ROS) play a crucial role in cell signaling, but excessive ROS levels lead to oxidative stress, which contributes to various diseases, including hypertension. This complex condition involves the interplay of multiple systems, including the heart, vasculature, kidneys, brain, and immune cells, where oxidative stress acts as a unifying factor. Despite evidence linking oxidative stress to hypertension, clinical trials using ROS scavengers and antioxidants have yielded inconsistent results, highlighting the need for a deeper understanding of redox mechanisms.

Recent research highlights the role of the endoplasmic reticulum (ER) in oxidative stress and hypertension. The ER is responsible for essential cellular processes, and stressors like oxidative stress can lead to ER stress, activating the unfolded protein response (UPR). While the UPR initially promotes cell survival, prolonged activation can lead to detrimental effects, including apoptosis, inflammation, and fibrosis. The interconnectedness of oxidative stress and ER stress is crucial in hypertension, with ER stress influencing endothelial dysfunction, cardiovascular remodeling, and kidney damage. Inhibition of ER stress has been shown to improve vascular function and reduce blood pressure in experimental models.

Understanding the intricate interactions between oxidative stress and ER stress is vital for elucidating the underlying mechanisms of redox-dependent processes in hypertension. Further research in this area could provide valuable insights for the development of novel therapeutic strategies to address hypertension and associated cardiovascular dysfunction.

A Primer in Oxidative Stress ROS are generated by the incomplete reduction of molecular oxygen (O2) and can be either free radicals or nonradicals. They are produced through metabolic and enzymatic reactions within cells, with NADPH oxidase being the major source in the cardiovascular and renal system. The intracellular redox state is regulated by antioxidant systems, which maintain redox homeostasis. These systems include enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase, peroxiredoxins, and the thioredoxin system. The transcription factor Nrf2 plays a key role in regulating antioxidant enzymes and genes involved in antioxidant and anti-inflammatory processes.

Reactive oxygen species (ROS) play a vital role as secondary messengers in cellular signalling. The oxidation of specific residues in proteins regulates the activation or inactivation of receptors, enzymes, transcription factors, ion channels, kinases, and phosphatases. These molecular processes are essential for fundamental cellular functions such as proliferation, differentiation, and apoptosis. However, ROS are highly reactive, and an increase in their availability leads to oxidative stress, which is associated with dysregulated redox signalling reversible and irreversible protein oxidation, and damage to lipids and DNA.1 Many of these processes contribute to cardiac, vascular, and renal injury, which are associated with the development of hypertension. Oxidative stress has been implicated in the pathophysiology of several diseases, including hypertension.2 Complex interaction between multiple systems involving the heart, vasculature, kidneys, brain, and immune cells is involved in hypertension, and oxidative stress is considered to be a unifying factor linking these elements.3 Oxidative stress is associated with alterations in all these systems, including endothelial dysfunction, cardiovascular remodelling, renal dysfunction, sympathetic nervous system activation, systemic inflammation, and immune cell activation.3 Despite experimental evidence supporting the involvement of oxidative stress in hypertension, with studies showing antihypertensive effects of various antioxidants in experimental models, attempts to reduce ROS bioavailability with the use of ROS scavengers and antioxidant vitamins have yielded inconsistent results in clinical trials.4,5 On the other hand, the antioxidant coenzyme Q10 may have cardiovascular protective effects in patients with hypertension.6 Reasons for discrepant findings in the clinic may relate to poor bioavailability and variable pharmacokinetic properties of different antioxidants, highlighting the need for a deeper understanding of redox mechanisms to better target oxidative stress. Recent advances in redox biology have provided new insights into specific redox-sensitive targets in cardiovascular pathophysiology. In addition, new molecular mechanisms contributing to oxidative stress in hypertension have come to light, including the role of the endoplasmic reticulum (ER).7 The ER is an essential intracellular membraneebound organelle responsible for vital cellular processes such as protein folding, synthesis, trafficking, calcium homeostasis, and lipid production.8 Various cellular stressors, including oxidative stress, disturbances in calcium balance, and increased protein synthesis demands, cause accumulation of unfolded proteins, leading to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to adapt to and restore ER homeostasis.7 Initially, the UPR promotes a prosurvival and adaptive response, aiming to maintain cellular functions. However, prolonged activation of the UPR can lead to detrimental effects such as apoptotic cell death, inflammation, and fibrosis.7 Importantly, oxidative stress and ER stress are intricately connected: oxidative stress can affect ER function and activate the UPR, and conversely, ER stress can induce ROS generation, which further contributes to oxidative stress.7,8 In the context of hypertension, ER stress has emerged as a novel player.9 It influences endothelial dysfunction, cardiovascular remodelling, and kidney damage associated with hypertension. In addition, inhibition of ER stress improves vascular function, reduces vascular remodelling, and lowers blood pressure in experimental models of hypertension.9 The interplay between oxidative stress and ER stress has been demonstrated in experimental hypertension and is of importance in hypertension-associated cardiovascular dysfunction and target organ damage. Understanding the interactions between these systems may provide new insights into mechanisms underlying redox-dependent processes in hypertension.

A Primer in Oxidative Stress ROS play a crucial role in the physiologic regulation of all cell functions through oxidative post-translational modification of redox-sensitive residues in proteins, such as cysteine, methionine, histidine, and lysine.10 A major redox signalling mechanism involves the oxidation of cysteine residues within proteins, which can result in the formation of sulfenic acid. Further oxidation can lead to the formation of disulfide bonds and glutathionylation, among other reversible modifications.11 Redox-sensitive signalling operates in conjunction with other signalling processes, such as protein phosphorylation and calcium (Ca2þ) signalling, to finely regulate numerous cellular processes, including proliferation, migration, differentiation, inflammation, extracellular matrix deposition.12 However, when ROS levels become abnormally elevated due to increased ROS generation and/or impaired antioxidant capacity, oxidative stress is induced, leading to pathological signalling and damage to proteins, lipids, and DNA.10 ROS are produced by the incomplete reduction of molecular oxygen (O2) and include both free radicals, such as superoxide anions (O2 C) and hydroxyl radicals (OH), and nonradicals, such as hydrogen peroxide (H2O2). O2 C is typically short lived because it is rapidly reduced by superoxide dismutase (SOD) to form H2O2. Moreover, O2 C can react with nitric oxide (NO) to generate peroxynitrite (OONO), contributing to molecular damage associated with oxidative stress.1,10-12 H2O2, a nonradical ROS, is relatively stable and plays an important role in redox signalling. ROS production is mediated by metabolic and enzymatic reactions within cells (Fig. 1). Single-electron reduction of O2 by mitochondrial electron transport is an important source of O2 C. 13 In addition, H2O2 is generated as part of the oxidative protein-folding process in the ER.14 More than 40 ROS-generating enzymes have been identified in human cells, including xanthine oxidase, uncoupled nitric oxide synthase (NOS), cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes, among others. However, ROS generated by these systems occur as a byproduct of enzymatic reactions. The only known oxidase that generates ROS as its primary function is NADPH oxidase (NOX), which is the major source of O2 C and H2O2 in the cardiovascular and renal system.15 The intracellular redox state is also regulated by many antioxidant systems, which maintains redox homeostasis. Antioxidant enzymes such as SOD play a significant role in protecting cells against oxidative stress by rapidly converting O2 C into H2O2, which is targeted by catalase, resulting in the formation of H2O and O2. 16 Other systems, such as glutathione peroxidase and peroxiredoxins, can also scavenge H2O2. In addition, the thioredoxin system can reduce oxidised cysteine residues in proteins, such as peroxiredoxins, to restore antioxidant function.17 The master regulator of antioxidant enzymes is the transcription factor nuclear factor erythroid 2erelated factor 2 (Nrf2).18 Nrf2 regulates genes containing antioxidant response elements (AREs) in their promoters.18 Accordingly Nrf2 regulates expression of many genes involved in antioxidant and antiinflammatory processes in cells. Among the major Nrf2-regulated antioxidant genes important in vascular function are superoxide dismutase, catalase, glutathione peroxidase, peroxiredoxin, thioredoxin, and heme oxygenase