Physiological Roles of Oxidative Stress in Cardiovascular Tissues

       Under physiological conditions, low levels of ROS production are equivalent to their detoxification and play a major role in cellular signaling and function ^[2]. This process is called redox signaling and is defined as the specific and reversible oxidation/reduction modification of cellular signaling components able to regulate gene expression, excitation–contraction coupling, or cell growth, migration, differentiation, and death ^[3][4] (Figure 1).

Figure 1. Physiological roles of oxidative stress in cardiovascular tissues. Black arrow represents activation and red arrow represents inhibition. p38 MAPK: p38 mitogen-activated protein kinase; JNK: c-Jun N-terminal kinase; H₂O₂: hydrogen peroxide; NFκB: nuclear factor-kappa beta; CAMKII: Ca/calmodulin-dependent kinase II; RyR: ryanodine receptor; PKA: cAMP-induced protein kinase A; NO: nitric oxide; PKG: protein kinase G; Nrf2: nuclear factor erythroid 2-related factor 2.

       Several kinases are involved in redox signaling. For instance, H₂O₂ could activate Ca/calmodulin-dependent kinase II (CAMKII), leading to excitation–contraction coupling ^[4] or p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNKs) leading to inhibition of insulin signal transduction. cAMP-induced protein kinase A (PKA) is also activated by oxidation of its regulatory subunit R1α and translocated from cytosol to membrane, where PKA regulates cardiac excitation–contraction coupling in the heart and vasodilation in the vessels ^[4].

       Many transcription factors are also regulated by redox signaling. As an example, the nuclear factor-kappa beta (NFκB) is activated when ROS have damaged its inhibitor (IkB) and regulates inflammation process ^[5]. The nuclear factor erythroid 2-related factor 2 (Nrf2) could be induced by lipid peroxidation to activate several key antioxidant enzymes containing an antioxidant/electrophile response element motif in their promoter, such as heme oxygenase 1, glutathione peroxidases, SOD, peroxiredoxins, thioredoxins, and thioredoxin reductases ^[6]. In detail, under unstressed conditions, Nrf2 is constitutively ubiquitinated by both Kelch-k-like ECH-associated protein 1 (Keap1) and Cullin-3 E3 ligase to be damaged ^[6][7]. The activation of Nrf2 is due to the oxidation of Keap1 that abrogated its negative control on Nrf2.

       Under physiological conditions, NO is a cytoprotective molecule with a vasodilator action. NO inhibits the activation and adhesion of platelets and neutrophils and has protective effects against ischemia reperfusion and heart failure ^[8]. NO could exert its biological effects by binding to the soluble guanylate cyclase in order to produce cyclic guanosine monophosphate leading to protein kinase G (PKG) activation ^[9] or by S-nitrosylation. This latter modification could modulate several protein activities such as pro-caspase 3, myosin heavy chain, tropomyosin, peroxiredoxins, or ryanodine receptor (RyR). RyR, which mediates Ca²⁺ release from sarcoplasmic reticulum, is also activated by phosphorylation via PKA and CAMKII, themselves redox-regulated ^[4]. Moreover, PKG is activated by oxidation independently of NO and regulates vascular tone and cardiomyocyte contraction or hypertrophy ^[4].