Resolvin D1 as a novel target in the management of hypertension

Hypertension afflicts more than 1.4 billion people worldwide and remains a leading global public health concern, especially in light of the deaths and disability from cardiovascular disease and stroke due to hypertension-mediated organ damage. Hypertension is generally divided into primary and secondary hypertension. Unlike secondary hypertension, primary hypertension lacks identified causes, and it is a multifactorial disease involving genetic factors, sex, hormonal status, environmental factors, and behavioral risk factors. Three theories have provided commonly accepted therapeutic targets for hypertension: salt absorption, the renin–angiotensin–aldosterone system (RAAS), and sympathetic nervous system (SNS) activation. However, despite the availability of five classical antihypertensive agents, fully half of the hypertensive population is still unable to effectively control their blood pressure. The investigation and identification of new therapeutic targets for the treatment of hypertension are thus required. With the increase in the number of approaches to the treatment of hypertension, recent international research has highlighted new drug therapeutic targets [including the nitric oxide (NO) pathway, the brain's renin–angiotensin system (RAS), leptin, sodium-glucose cotransporter 2 (SGLT2), endothelin receptor, and more], biotherapy (e.g., vaccines, gastrointestinal microbiota), and mechanotherapy (carotid baroreceptor stimulation, arteriovenous fistula) [1,2]. However, the selectivity and efficacy of drugs targeting newly identified targets remain unknown. Vascular remodeling is both a cause and a consequence of hypertension, involving artery structural stiffening and arterial wall primary cell [endothelial cell, smooth muscle cell (SMC), and fibroblast] dysfunction due to the changes in the cells’ mechanical environment [3]. Recent comprehensive reviews have considered much of this research [4,5]. As the main effector molecule of the RAS, angiotensin II (AngII) is a regulator of vasoconstriction, cell proliferation, organ hypertrophy, water and sodium retention, and the release of aldosterone in the development and presence of hypertension. In this issue of the Journal of Hypertension, Cheng et al. report their intriguing observation in a mouse model that the inhibition of RhoA/MAPK activity by resolvin D1 may be a potential therapeutic target in AngII-induced hypertension [6], and they provide two pieces of new information: resolvin D1 prevented the switch to the vascular smooth muscle cell (VSMC) phenotype caused by AngII, and resolvin D1 ameliorated AngII-induced induced vascular extracellular matrix (ECM) remodeling. RhoA is a member of the family of small GTPases that includes RhoA, Rac1, and cdc42. RhoA acts as a molecular switch due to its GTPase activity, which cycles RhoA between an active GTP-bound state and an inactive GDP-bound state [7]. The modulation of a RhoA/ROCK-mediated VSMC contraction process is an integral part of the VSMC phenotype switch. A 2019 study revealed that the use of alkaloids from Nelumbinis Plumula resulted in anti-AngII-induced hypertension via an inhibition of VSMC cytoskeleton remodeling and the regulation of the RhoA/ROCK pathway [8]. A study using a rat model demonstrated that high salt intake augmented the activity of the RhoA/ROCK pathway, which robustly induced VSMC contractions by directly phosphorylating and inhibiting the activity of myosin light-chain phosphatase [9]. In this issue of the Journal, Cheng et al. report their observation that resolvin D1 ameliorates both the AngII-induced VSMC phenotype switch from contractile VSMCs to VSMCs and cell migration and proliferation by a modification of RhoA/MAPK pathway, thus providing a new potential target for treating hypertension. Their findings emphasize the need to further clarify the phenotypic differences among SMCs. Aside from VSMC phenotype switching, the vascular ECM is also well known for its ability to form an intricate three-dimensional network that provides mechanical support for various cell types and maintains vascular wall integrity. Many investigations have demonstrated that the vascular ECM plays a critical role in hypertension and hypertension-associated vascular remodeling, including alterations in ECM components and the ECM's topological arrangement [10,11]. It was revealed that vascular oxidase stress, inflammation, and collagen deposition are the main causes of vascular remodeling in AngII-induced hypertension [12,13]. Although the RhoA/ROCK pathway as a main therapeutic target in vascular ECM remodeling has rarely been discussed, RhoA within myofibers has been demonstrated to impact the ECM's organization in terms of tortuosity and assembly by the control of Erk1/2 activation and the expression of ECM regulators such as Mmp9/Mmp13/Adam8 and macrophage chemo-attractants such as Ccl3/Cx3cl1 in adult skeletal muscle in a cell-autonomous manner [14]. In addition, the Cheng et al. study shows that resolvin D1 reduced collagen deposition and improved vascular fibrosis in AngII-induced vascular damage, indicating that resolvin D1 could be a potential target for improving AngII-induced vascular remodeling. Moreover, multiple studies have documented that resolvin D1 elicits potent anti-inflammatory effects in various pathological models [15], and increasing evidence indicates that inflammation and innate immune disorder play important roles in vascular remodeling and contribute to the deleterious consequences of hypertension [16]. Related research suggests that T-cell-derived miR-214 regulates the production of several profibrotic cytokines such as interleukin-9, interleukin-17, interferon-γ, tumor necrosis factor-α and a number of chemokines that mediate perivascular fibrosis in AngII-induced hypertension [17]. In addition, Olivares-Silva et al. reported that resolvin D1's attenuation of AngII-induced cardiac inflammation in mice was associated with the prevention of cardiac remodeling and hypertension [18]. Based on the above-described findings, we have concluded that resolvin D1 could alleviate, at least in part, AngII-induced inflammation-related vascular remodeling by the RhoA/MAPK pathway. Although the Cheng et al. study did not examine the anti-inflammation effect of resolvin D1 in detail, their valuable work provides a new research direction for future research. Of course, the results presented by Cheng et al. are only the beginning of the studies of this exciting new target for the therapeutic control of experimental hypertension by the modification of RhoA/MAPK activity [6]. Given the potent anti-vascular remodeling effect of resolvin D1 in AngII-induced hypertension, several issues regarding RhoA/MAPK as a promising therapeutic target should be investigated. Only an AngII-induced hypertension animal model has been used in this context, and the topics of salt absorption and SNS activation-related hypertension merit further investigation. Another potential limitation is that Cheng and his colleagues used only the RhoA agonist U46619 to identify the antihypertensive effect of resolvin D1 through the RhoA/MAPK signaling pathway, and current study lacks the genetic gain of function and pharmacological activations of biological activity. In conclusion, these findings suggest resolvin D1 as a new promising therapeutic target for the treatment of AngII-induced hypertension, and vascular remodeling (which has frequently been overlooked) is receiving renewed attention (Fig. 1). Future studies should focus on the clinical efficacy and safety of resolvin D1 in patients with essential hypertension. Addressing the questions mentioned above will also better guide the clinical evaluation and care of patients with hypertension.FIGURE 1: Proposed mechanisms of the resolvin D1-mediated amelioration of AngII-induced hypertension. α-SMC, alpha-smooth muscle actin; AngII, angiotensin II; AT1, angiotensin receptor 1; ERK, extracellular signal-regulated kinases; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; OPN, osteopontin; p38, p38 mitogen-activated protein kinase; REK, Rhein-Erft-Kreis; RvD1, resolvin D1; SM22α, smooth muscle-22alpha; VSMCs, vascular smooth muscle cells.ACKNOWLEDGEMENTS Funding: This work was supported in part by grants from the National Natural Science Foundation of China (nos. 81770485, 8216087, and 82370424). Conflicts of interest There are no conflicts of interest.