Reactive oxygen species (ROS) are considered highly reactive molecules that, depending on the amount produced, can affect cells and vascular functions [1]. Their precise regulation of production in the endothelium is crucial for controlling various cell functions in the vascular system ^[2][3][4][2,3,4]. Otherwise, excessive production of ROS (including superoxide O₂^_, hydroxyl radical ^_OH, and peroxynitrite anion ONOO^_) can cause the disruption of redox homeostasis, damage the immune system response, and favour the manifestation of vascular diseases ^[5][6][5,6]. This situation can occur in various circumstances where there is an imbalance between ROS generation and antioxidant defence mechanisms, such as chronic inflammation, ischemia-reperfusion injury, aging, and metabolic disorders. Another important factor is impaired endothelial function (since endothelium is the main source of ROS), which disrupts the production of protective blood agents and contributes to cytotoxic effects, cell death, and, inevitably, oxidative stress ^[7][8][7,8]. Interestingly, it is worth noting that ROS have beneficial effects due to their cytotoxic properties and can serve as a defence mechanism against infections [9].

As for the overproduction of ROS in the development of cardiovascular disease, damage to the cardiovascular system caused by oxidative stress favours diseases such as hypertension, atherosclerosis, and heart failure ^[10][11][10,11]. The renin-angiotensin system (RAS) interacts with ROS and contributes to these diseases. Angiotensin II (Ang II), as a key component of the RAS, plays an important role in this interaction as it can stimulate ROS production through various mechanisms, such as activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase through its binding to the AT1 receptor (AT1R) [10]. This overproduction of ROS over Ang II can in turn affect the activity of components of the RAS, such as increase in the expression of the Angiotensin I to ACE and the production of renin.

2. Physiology of the RAS in Vascular Regulation

Understanding the physiology of RAS is vital for comprehending the interplay between ROS and RAS in vascular regulation. Increased levels of Ang II, the main effector of the RAS molecule, play a crucial role in cardiovascular disease progression when its production or signaling becomes dysregulated ^[10][11][10,11]. The physiological intricacies of the RAS have been thoroughly examined and comprehensively expounded upon in previous scientific investigations [10]. However, in the context of theour present research on the influence of ROS in the progression of cardiovascular diseases, it is imperative to revisit and restate the fundamental principles of RAS physiology. By revisiting this well-established foundation, the researchers'our objective is to establish a cohesive link between the RAS and the role of ROS in the development and manifestation of cardiovascular disorders. The release of renin (an enzyme produced by conditions of reduced perfusion such as low blood pressure, low blood volume, or sympathetic stimulation), will activate a sequential processing of glycoprotein angiotensinogen (AGT), leading to the production of the decapeptide Ang I [12]. Subsequently, Ang I is further cleaved by ACE, a membrane-bound metalloprotease, and converts to Ang II. Once Ang II is formed it binds G-protein-coupled receptors (AT1-4R) ^[13][14][15][13,14,15]. AT1Rs are the prime mediators of Ang II leading to vasoconstriction, aldosterone and vasopressin secretion, and sodium and water retention. Because of this, AT1Rs play a crucial role in cardiovascular regulation, inflammation, fibrosis, endothelial dysfunction, and organ damage like nephrosclerosis ^[16][17][16,17]. On the other hand, the effects of AT2-4Rs are not fully understood, but they act differently than AT1Rs. It is believed that AT2Rs, when activated, counteract the short- and long-term effects of AT1Rs leading to beneficial antiproliferative and vasodilatory effects [18]. Other potential effects of AT2Rs include the regulation of cell growth and processing of the neuronal tissue [19]. AT3Rs were recently discovered and their exact role has not been elucidated. AT4Rs play a protective role in thrombotic effects as a fibrinolysis buffer by controlling the production of plasminogen activator inhibitor-1 (PAI-1). The nature of AT4Rs has been extensively investigated in the past with insulin-regulated aminopeptidase (IRAP) being the prominent candidate [20]. Angiotensin IV not only inhibits the peptidase activity of this enzyme but also facilitates IRAP translocation to the cell surface and enhances insulin-mediated glucose uptake [20]. In addition to the impacts mediated by G-protein-coupled receptors, recent discoveries of alternative enzyme systems and novel effector peptides have broadened our conventional understanding [21]. Among these systems are the receptors for prorenin and the G-protein-coupled receptor MAS [22]. The identification of these systems enhances our understanding of the intricate nature of the RAS by revealing that prorenin can activate renin and subsequently trigger protein kinases ERK1 and ERK2 ^[23][24][23,24]. The activation of these receptors introduces additional proliferative and metabolic effects that are not dependent on Ang II [25]. For blood pressure regulation, Ang II fast response to vascular changes is important. G protein-depended pathways enhance smooth muscle cell contraction [26] and trigger molecules that will contract smooth muscle cells. Moreover, when Ang II activates the G protein, it triggers the activation of phospholipase C, which leads to the production of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol. These molecules then initiate the release of calcium ions (Ca²⁺) into the cytoplasm. The binding of Ca²⁺ to calmodulin activates myosin, a protein involved in muscle contraction, and enhances its interaction with actin. As a result, smooth muscle cells contract, contributing to the modulation of blood pressure. The provided section of physiology elucidates the mechanism behind blood pressure regulation, which are mainly regulated by the rapid action of Ang II. By activating smooth muscle cell contraction through the G protein-dependent pathway, Ang II triggers a cascade of events involving phospholipase C, inositol-1,4,5-trisphosphate (IP3), diacylglycerol, and calcium ions (Ca²⁺). This series of molecular interactions ultimately leads to the contraction of smooth muscle cells. Understanding these intricate processes helps us grasp the physiological basis of blood pressure adjustments in response to changes in posture.

3. Pathological Implications of the RAS and the Involvement of ROS

As established thus far, the pathological manifestations of the RAS (abnormal cellular proliferation, inflammation, disrupted vascular balance) are closely related to the excessive presence and prolonged exposure of Ang II [27]. ROS, such as O₂^•_ (superoxide) and H₂O₂ (hydrogen peroxide), contribute to these pathological processes through Ang II signaling ^{[28][29][30][31]}[28,29,30,31]. In the cardiovascular system, Ang II contributes significantly to hypertension through its central, vascular, or renal effects. The multimeric enzyme of NADPH oxidase-derived ROS production is a deleterious equation in the development of Ang II-induced hypertension. NAPDH oxidase induces Ang II-induced oxidative stress, due to increased enzymatic activity. This occurs because of the rapid translocation and phosphorylation of cytosolic subunits of the small GTPase rac1 and p47phox to the cytochrome complex, via protein kinase C (PKC) ^[32][33][32,33]. Thereafter, PKC activates Janus kinase (JAK), which transduces and activates the JAK/STAT signaling pathway. This sequence promotes Ang II multiplication processes. Other components in revealing Ang II adverse effects are the early growth responsive genes and redox-sensitive proteins (c-Src, epidermal growth factor EGFR) ^[34][35][36][34,35,36]. Specifically, EGFR activates the Ras/Raf/ERK cascade, which subsequently upregulates c-Fos. Together with c-Jun, activated by c-Src via JNK, c-Fos forms the transcription factor known as activator protein-1 (AP-q1) [33]. Elevated levels of Ang II can have additional consequences on cellular viability and potentially induce DNA damage. The increased presence of O₂^•_ and H₂O₂ activates additional redox-sensitive proteins, including p38/MAPK, which in turn stimulates the pro-survival factor Akt ^[37][38][37,38]. In a cascade of subsequent reactions, Akt inhibits various pro-apoptotic proteins. Another essential mediator of the RAS is aldosterone, which plays a crucial role in maintaining sodium and potassium balance, thus influencing extracellular volume. Aldosterone also exhibits potent pro-fibrotic effects [39]. The release of aldosterone is triggered by Ang II, and emerging evidence suggests that aldosterone may contribute to and exacerbate the detrimental effects of Ang II. Through activation of mineralocorticoid receptors, aldosterone promotes endothelial dysfunction and thrombosis, reduces vascular compliance and baroreceptor function, and induces fibrosis in both myocardial and vascular tissues [40]. The resulting increase in blood pressure and circulating volume, caused by the effects of Ang II and aldosterone on their target organs, establishes a negative feedback loop that suppresses renin release. The maintenance of this feedback inhibition critically relies on the Ang II-mediated activation of the AT1R [41]. Understanding the pathological effects of the RAS and the involvement of ROS is crucial for several reasons. It provides insights into the molecular mechanisms underlying cardiovascular diseases associated with RAS dysregulation, aiding in the advancement of precision therapeutic interventions. The identification of specific proteins and pathways involved opens opportunities for drug development, enabling the design of medications that selectively target these molecules or their associated receptors. This knowledge also contributes to personalized medicine approaches, considering individual variability in RAS responses. Moreover, it drives research advancements by uncovering novel signaling pathways and potential biomarkers, enhancing our understanding of cardiovascular disease pathophysiology. Overall, comprehending the pathological effects of RAS and ROS has significant implications for improving patient outcomes and advancing cardiovascular research.

4. The Application of ACEIs and ARBs in the Treatment of Cardiovascular Disorders

For a considerable period, the ACE/Ang II/AT1R pathway was recognized as the primary mechanism through which the RAS influences cardiovascular processes. Various categories of antihypertensive medications, including ACEIs, ARBs, β blockers (BBs), direct renin inhibitors (DRIs), and mineralocorticoid receptor antagonists (MRAs), have been employed to provide cardiorenal protection. ACEIs and ARBs, along with BBs, DRIs, and MRAs, act by interfering with the signaling pathways within the RAS. They are considered the first-line treatment options for managing hypertension and other cardiovascular disorders such as heart failure ^[42][43][44][42,43,44]. Furthermore, ACEIs and ARBs have a significant impact on the cardiovascular system and offer a protective effect against the occurrence and progression of kidney disease [45]. In addition to the well-established protection that ACEIs offer to the cardiovascular and renal systems by effectively controlling arterial pressure thresholds, they have also been associated with additional beneficial effects on the endothelium [46]. This has been confirmed in research studies conducted on patients with coronary artery disease or hypercholesterolemia, regardless of the effect on blood pressure reduction. These studies demonstrate that ACEIs and ARBs can additionally improve endothelial and vascular function in these patients. Furthermore, large studies have shown that ACEIs and ARBs are effective as monotherapy in managing other conditions such as left ventricular hypertrophy, systolic dysfunction, heart failure, and myocardial infarction [47]. Additionally, trials like the HOPE study, ONTARGET, and TRANSCEND have reported the extended benefits of ACEIs and ARBs to patients with an increased susceptibility to adverse outcomes but without left ventricular dysfunction [48]. For instance, the HOPE trial showed that ramipril significantly reduced the incidence of death, myocardial infarction, and stroke in high-risk patients [49]. Similarly, the EUROPA trial revealed a relative risk reduction in cardiovascular events with perindopril treatment in patients with stable coronary heart disease. However, the PEACE trial, which focused on stable coronary artery disease patients with preserved ventricular function, did not find a therapeutic benefit of ACEIs when added to conventional therapy, potentially because of the minimal occurrence of significant outcome events in that patient group ^[47][50][47,50].

5. Enhancing Endothelial Function and Mitigating Oxidative Stress: Exploring the Effects of ACEIs and ARBs

Several studies have demonstrated the favourable effects of ACEIs and ARBs on endothelial function and their ability to control oxidative stress levels in populations with cardiovascular diseases. As it has already been cleared, Ang II excessive presence is thought to play a pivotal role in the increased generation of O₂^•_ and the impairment of endothelial function in blood vessels. This effect is achieved through the activation of NADPH oxidases, triggered by the stimulation of AT1 receptors [51]. Additionally, studies conducted in laboratory settings have revealed that AT1 receptors can be upregulated by low-density lipoproteins ^[52][53][52,53]. By augmenting the activity of SOD3 and blocking NADPH oxidase activation, ACEIs and ARBs provide an indirect mitigation of oxidative stress ^[46][54][46,54]. In patients with coronary artery disease, it has been observed that ramipril (ACEI) and losartan (ARB) improve endothelial function by increasing the availability of nitric oxide (NO) through the mitigation of oxidative stress within the arterial wall ^[55][62]. Additionally, ARBs offer vascular protective effects ^[56][63]. Losartan promotes the phosphorylation of endothelial NO synthase (eNOS) and suppresses endothelial apoptosis induced by Tissue Necrosis Factor-α (TNF-α) through the activation of the VEGFR2/PI3K/Akt pathway ^[57][61]. Additionally, in diabetic rats, losartan restored glomerular NO production by increasing GCH1 protein expression and tetrahydrobiopterin (BH4) levels ^[58][64]. Furthermore, valsartan and irbesartan (ARBs) exert effects that counteract the development of atherosclerosis. The promotion of eNOS Ser117-phosphorylation increases eNOS mRNA stability and this leads to the reduced NADPH oxidase expression and also to the augmented vascular BH4 and restored eNOS uncoupling ^[59][60][65,66]. Some of the positive effects of ACEIs may be attributed to their impact on an ACE signaling cascade, resulting in improved endothelial function that appears to be independent of their effects on vasoactive substances ^[61][68]. Another mechanism suggested to beneficially affect the endothelium is the introduction of ACEIs as a treatment, with potential ACE signaling cascade involvement. This effect seems unrelated to the impact of ACEIs on vasoactive substances ^[62][69]. Moreover, when ACEI binds to the cell surface ectoenzyme ACE, it triggers a cascade that ultimately increases ACE and cyclooxygenase-2 expression. Firstly, ACEI binding activates casein kinase 2, leading to serine residue phosphorylation at the molecule’s C-terminal end ^[62][69]. Secondly, ACE-associated c-Jun N-terminal kinase is activated, possibly through mitogen-activated protein kinase 7 activation ^[63][70]. This cascade eventually leads to an increase in the expression of ACE and cyclooxygenase-2 (through the accumulation of phosphorylated c-Jun in the nucleus, enhancing the DNA-binding activity of activator protein-1) ^[64][71]. Additionally, the elevated expression of cyclooxygenase-2 benefits endothelial function by promoting the production of prostacyclin, a vasodilator and antiplatelet agent, by endothelial cells ^[65][72]. To conclude this section, it is evident that ACEIs and ARBs have shown potential in modulating ADMA metabolism and improving endothelial function. These drugs may reduce ADMA levels through various mechanisms, including activation of DDAH and attenuation of oxidative stress. However, further research is required to fully elucidate the precise mechanisms involved. Understanding the impact of ACEIs and ARBs on ADMA metabolism contributes to our knowledge of their potential benefits in cardiovascular health and warrants continued investigation in this field.