Despite strong indications that increased consumption of added sugars correlates with greater risks of developing cardiometabolic syndrome (CMS) and cardiovascular disease (CVD), independent of the caloric intake, the worldwide sugar consumption remains high. In considering the negative health impact of overconsumption of dietary sugars, increased attention is recently being given to the role of the fructose component of high-sugar foods in driving CMS. The primary organs capable of metabolizing fructose include liver, small intestine, and kidneys. In these organs, fructose metabolism is initiated by ketohexokinase (KHK) isoform C of the central fructose-metabolizing enzyme KHK. Emerging data suggest that this tissue restriction of fructose metabolism can be rescinded in oxygen-deprived environments. In this review, we highlight recent progress in understanding how fructose metabolism contributes to the development of major systemic pathologies that cooperatively promote CMS and CVD, reference recent insights into microenvironmental control of fructose metabolism under stress conditions and discuss how this understanding is shaping preventive actions and therapeutic approaches.

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.

In Figure 7H, the Vehicle+Fc flow cytometry panel was incorrect. In Figure 9M, the ANGII+DEL-1-FC panel was incorrect. In Figure 10M, the ANGII+DEL-1-RGE-Fc was incorrect. The correct images, provided from the original source data, are shown below.

Sepsis is a complex clinical syndrome with high lethality characterized by systemic inflammation and organ failure.[1] Although intensive research over the past decades has identified several mechanisms contributing to sepsis pathology, sepsis represents a major therapeutic burden. Current therapeutic strategies are limited to rapid initiation of antibiotic therapy and further supportive treatment, including fluids, the use of vasopressors and functional organ replacement.[2] Therefore, sepsis was recently identified by the World Health Organization as a global health priority.[3] In the context of sepsis pathogenesis and progression, an important mechanism is vascular leakage due to disruption of the vascular barrier by inflammatory stimuli.[4] [5] Maintenance of vascular integrity is supported by the efficient removal of apoptotic endothelial cells. The phagocytic clearance of damaged cells by macrophages, a process termed efferocytosis, induces resolution of inflammation and suppression of pro-inflammatory cytokines.[6] [7] In the previous issue of Thrombosis and Haemostasis, Lee et al[8] proposed a new mechanism, by which macrophage Stabilin-1 (STAB-1), a phagocytic receptor mediating efferocytosis by recognizing phosphatidylserine on apoptotic cells,[9] promotes the clearance of apoptotic vascular endothelial cells damaged by severe inflammation. This function of STAB-1 protects against disruption of vascular integrity in the course of sepsis.[8] Low pH values, which are present in patients with septic shock, promote the macrophage expression of STAB-1.[9] Genetic deletion of STAB-1 decreased the survival of septic mice in the model of cecal ligation and puncture. Decreased sepsis survival in STAB-1 deficiency was associated with diminished efferocytosis, increased vascular permeability and enhanced organ dysfunction. Interestingly, the pro-inflammatory mediator high-mobility group box 1 (HMGB1)[10] [11] [12] inhibited STAB-1-dependent efferocytosis of apoptotic cells. Consistently, blockade of HMGB1 with a neutralizing antibody improved the phagocytic capacity of macrophages and reduced sepsis mortality. Previous work by Palani et al[13] demonstrated that STAB-1 on monocytes suppresses the activation of Th1 lymphocytes; thus, STAB-1 may also exert an immunosuppressive action. In addition, STAB-1 may regulate lymphocyte migration and inflammatory cell recruitment.[14] How the sepsis-protective action of STAB-1, as shown by Lee et al in this issue of Thrombosis and Haemostasis,[8] may reconcile with its previously described immunomodulatory functions, requires future investigation. Thus, a therapeutic approach aiming at increasing STAB-1 function needs to be carefully evaluated. Taken together, the study by Lee et al demonstrated the important role of macrophage STAB-1 in protecting against vascular barrier dysfunction in sepsis via mediating enhanced efferocytosis of apoptotic endothelium.[8] Testing the proposed sepsis-protective mechanism of STAB-1 merits further experimental and pre-clinical assessment.