Abstract 117: Interleukin-18 Is A Critical Mediator Of Cardiac Remodelling During Angiotensin II-induced Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2022-09, Vol.79 (Suppl_1)
• Main Authors: Drummond, Grant, Saini, Narbada, Georgia-Sherriff, Ashleigh, Diep, Henry, Pinto, Alexander, Dona, Malathi, Sobey, Christopher G, Jelinic, Maria, Vinh, Antony
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.79.suppl_1.117

Abstract only Hypertensive heart failure is characterised by cardiomyocyte hypertrophy, inflammation and fibrosis, leading to stiffening and diastolic dysfunction. There are currently no effective treatments for hypertensive heart failure, in part reflecting our limited knowledge of the molecular mechanisms. Interleukin-18 (IL-18) is a pro-inflammatory, inflammasome-derived cytokine that is elevated in the circulation of hypertensive patients; however, its role in promoting cardiac remodelling and dysfunction is unknown. Thus, we examined if IL-18-deficient ( Il18 -/- ) mice were protected from hypertensive cardiac remodelling and, if so, whether this occurs independently of changes in blood pressure. Hypertension was induced in male wild-type (WT) and Il18 -/- mice by angiotensin II (Ang II; 1.44 mg/kg/d, s.c. ) infusion for 28 d. Normotensive controls were saline-infused. Systolic blood pressure (SBP) was measured by tail cuff, gene expression was measured by single cell RNA sequencing (scRNA-seq), cardiac fibrosis by picrosirius red-staining, and cardiac hypertrophy/remodelling was assessed histologically and via heart weight:body weight. scRNAseq analysis of hearts isolated from Ang II-treated WT mice revealed that IL-18 was expressed by macrophages, granulocytes and epicardial cells. Baseline SBPs were not different between WT and Il18 -/- mice, and Ang II evoked a similar degree of hypertension in each genotype (160 ± 24 and 165 ± 16 mmHg in WT and Il18 -/- mice, respectively). Despite having no impact on pressor responses to Ang II, IL-18-deficiency provided marked protection against Ang II-induced cardiac hypertrophy (6.58 ± 0.53 cf. 7.87 ± 1.14 mg/g in Il18 -/- and WT, respectively; n≥7, P&lt0.01) and fibrosis (1.84 ± 0.18 cf. 4.06 ± 0.46 % in Il18 -/- and WT, respectively; n≥7, P&lt0.01). Furthermore, cardiac myocytes were enlarged, disorganised and displayed hyperchromatic nuclei in Ang II-treated WT mice, but not in Ang II-treated Il18 -/- mice. In conclusion, IL-18 deficiency protects against cardiac remodelling during hypertension, independent of an effect on SBP. These findings suggest that IL-18 is a driver of hypertensive cardiac remodelling and potential target for future therapies.