Beyond the numbers in treating hypertensive end-organ damage: role of formyl peptide receptor agonist Cmpd17b

Hypertension remains a major risk factor for mortality due to cardiovascular disease including heart failure, arterial blockage, stroke, and kidney disease. Whereas antihypertensive therapy with more aggressive treatment goals improves systolic and diastolic blood pressure numbers, residual cardiovascular risk remains, which leads to hypertensive end-organ damage.1 Thus, it is important to address underlying mechanisms such as inflammation rather than simply focusing on elevated blood pressure. Inflammation and immune cell activation using both human studies and experimental animal models have been implicated in hypertension-induced vascular dysfunction and end-organ damage.2 However, like placing a bandage over a gaping wound, current treatment options that target hypertension do not alleviate inflammation and other underlying pathogenic mechanisms leading to adverse cardiovascular outcomes. Several targetable mechanisms have been proposed to induce inflammation, vascular dysfunction, and end-organ damage. One such mechanism involves the formation of products of lipid oxidation known as isolevuglandins.3,4 Isolevuglandins adduct to lysins on proteins and form adducts and cross-linked proteins that act as neo-antigens and activate T cells,3 which migrate to the kidneys that leads to renal damage and vascular dysfunction. The formyl peptide receptor (FPR) is a G protein-coupled receptor known for its role in chemotaxis and has been implicated in hypertension-related inflammation.5 Understanding the mechanistic role of FPR in hypertension may provide a critical link to attenuate the residual cardiovascular risk posed by inflammation leading to end-organ damage (Figure 1). Effects of Cmpd17b on hypertension and associated cardiovascular damage. Cmpd17b activates the formyl peptide receptor to alleviate hypertension. Notably, Cmpd17b moderately lowers blood pressure, but significantly and selectively limits hypertension-induced remodelling of the thoracic aorta and left ventricular regions, and favourably regulates gene expression to impact proteins implicated in human hypertension. In this issue of Cardiovascular Research,6 Singh et al. propose a pro-resolving small-molecule FPR1/FPR2-agonist, compound 17b (Cmpd17b), as a potential treatment for chronic inflammatory insult in hypertension. Although the mechanism by which Cmpd17b activates intracellular cardioprotective signalling pathways after binding to FPR1/FPR2 has been established,7,8 Singh et al. asked whether Cmpd17b may also protect against hypertension-induced end-organ damage using a mouse model of chronic angiotensin II (Ang II) infusion. They found that whereas treatment with Cmpd17b moderately lowers blood pressure, it markedly improves structural remodelling and mitochondrial physiology in the heart and vasculature. Structural changes, such as cardiovascular hypertrophy and fibrosis, are common in hypertensive subjects.9 The study by Singh et al. found that treatment with Cmpd17b attenuated Ang II-induced cardiac hypertrophy and fibrotic collagen deposition in the left ventricle and abdominal aorta of mice. They performed in depth quantitative tissue proteomics, informatics, enrichment, and functional analyses in mice, human aortic smooth muscle cells, with parallel comparison to publicly available human datasets from patients with cardiovascular disease. They found that the therapeutic efficacy of Cmpd17b is associated with improvements in mitochondrial function and bioenergetics by reducing the production of reactive oxygen species (NDUFA7), structural remodelling (PCOL3, TIMP2), and resolution of inflammation (ANXA1, LGR6, FPR1, FPR2, IL1β, MCP1). These discoveries are consistent with previous reports that targeting FPR with a biased agonist could prevent vascular dysfunction and inflammation in pulmonary arterial hypertension, suggesting therapeutic options that are more effective than attenuating blood pressure elevation.10 In summary, the study by Singh et al. highlights the potential use of Cmpd17b as a therapeutic intervention against residual inflammation to improved cardiovascular function, structural remodelling, and end-organ damage beyond what can be explained by reductions in blood pressure. Combining Cmpd17b with existing antihypertensive therapies could synergistically improve hypertension management and improve cardiovascular outcomes. The limitations of the study have been appropriately acknowledged by the authors including a lack of a specific mechanistic linkage albeit many different potential targets are revealed from the proteomic and the transcriptomic analyses. Also, the cell-specific effects are lacking given the expression and a demonstrated role of the formylpeptide receptor family in different cell types including immune cells, and these can have a secondary effect on all the observed functional outcomes. In addition, it will be critical to consider whether Cmpd17b treatment differs with sex/gender and among racial groups, particularly in those genetically predisposed to cardiovascular dysfunction. Overall, the Singh study has contributed heavily to expanding our framework of understanding Cmpd17b therapeutic utility. This study was supported by the National Institutes of Health grants R01HL144941 (A.K.), D34HP16299, T32AI007281, T32GM14492, and T32HL00773 (C.F.A.), The UNCF/Bristol-Myers Squibb E.E. Just Faculty Fund (A.H.); from the Burroughs Wellcome Fund (BWF) Career Award at the Scientific Interface under award number 1021868.01 (A.H.); from the Chan Zuckerberg Initiative’s Donor-Advised Fund of the Silicon Valley Community Foundation (Science Diversity Leadership Grant #2022-253529; A.H.); and a research pilot sub-award under 5R25HL106365 (A.H.). No new data were generated or analysed in support of this research.