Purpose of review: Hypertension remains a global health and socioeconomic burden. Immune mechanisms are now recognized as integral part of the multifactorial etiology of hypertension and related organ damage. The present review addresses inflammatory pathways and immune targets in hypertension, which may be important for an immunomodulatory treatment of hypertension aside from lowering arterial pressure. Recent findings: Anti-inflammatory interventions targeting single interleukins or almost the entire immune system show different beneficial effects. While immunomodulation (targeting specific portion of immune system) shows beneficial outcomes in certain groups of hypertensives, this does not pertain to immunosuppression (targeting entire immune system). Immunomodulatory interventions improve outcomes of hypertension independent of arterial pressure. The studies reveal interleukins, such as interleukin (IL)-1β and IL-17 as targets of immunomodulation. Besides interleukins, targeting αvβ-3 integrin and matrix metalloproteinase-2 or using experimental cell-therapy demonstrate beneficial effects in hypertensive organ damage. The NLR family pyrin domain containing 3 (NLRP3) inflammasome/IL-1β/endothelial cell/T-cell axis seems to be an important mediator in sustained inflammation during hypertension. Summary: Although immunomodulation may be advantageous as a causal therapy in hypertension, targeting immune networks rather than single interleukins appears of major importance. Further research is required to better identify these networks and their links to human hypertension.

The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous antiinflammatory factor, in angiotensin II– (ANGII–) and deoxycorticosterone acetate–salt–induced (DOCA-salt–induced) cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1 mice) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening, and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy and interstitial and perivascular coronary fibrosis and improved left ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting α_vβ₃ integrin–dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized α_vβ₃ integrin–dependent CD25⁺FoxP3⁺ Treg numbers and IL-10 levels, which were associated with decreased recruitment of inflammatory cells and reduced production of proinflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.

Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure control, the disruption of which may lead to hypertension. Hypertension itself can also cause endothelial dysfunction, as endothelial cells are susceptible to haemodynamic changes. Although it is unclear which of those factors appear first, they create a vicious circle further damaging multiple organs, including the heart and vessels. There are also sex-specific differences in homeostatic functions of the endothelium regarding vessel tone regulation, which may contribute to differences in arterial blood pressure between men and women. Even more importantly, there are sex-differences in the development of endothelial dysfunction and vessel remodelling. Hence, an understanding of the mechanisms of endothelial dysfunction and its contribution to pathological vascular remodelling during hypertension is of critical importance. This review addresses immunological and metabolic aspects in mechanisms of endothelial dysfunction and the resulting mechanisms in vascular remodelling with respect to arterial hypertension, including the potential role of sex-specific differences.

Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of Fads2 ^−/− mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, FADS2 expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.

Background: Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is the major receptor for uptake of oxidized low‐density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX‐1 (sLOX‐1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX‐1 as well as the diagnostic and risk stratification potential of sLOX‐1 in patients with AAA. Methods and Results: Serum sLOX‐1 was assessed in a case–control study in AAA (n=104) and peripheral artery disease (n=104). sLOX‐1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (β=1.28, P =0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, β‐blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX‐1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX‐1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase‐3, smooth muscle actin, collagen, and macrophage content. Conclusions: In AAA, sLOX‐1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX‐1, although it was not useful for risk stratification. Aneurysmal LOX‐1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX‐1 is eventually not deleterious in human AAA and could counteract AAA rupture.