CRIP1 deficiency attenuates vascular inflammation and early arterial remodelling in hypertension

O. Schweigert (Lübeck)¹, J. D. Escobar (Hamburg)², T. Tong (Lübeck)³, T. Reinberger (Lübeck)¹, T. Zeller (Lübeck)^1
1Universitätsklinikum Schleswig-Holstein Institut für Kardiogenetik Lübeck, Deutschland; ²University Center of Cardiovascular Science, University Heart and Vascular Center Hamburg Department of Cardiology University Medical Center Hamburg, Hamburg Hamburg, Deutschland; ³Universität zu Lübeck Institut für Kardiogenetik Lübeck, Deutschland

BACKGROUND:
Hypertension, a leading risk factor for cardiovascular events, is increasingly recognized as a systemic, low-grade inflammatory condition affecting multiple organs. Hypertension-related inflammation triggers vascular remodelling leading to an impaired vascular function, thereby exacerbating hypertension. Recently, an altered expression of the monocytic, immune-regulatory molecule CRIP1 has been shown in immune cells from hypertensive mice. However, its precise role in hypertension-related inflammation remains unknown.

AIM:
This project aimed to further elucidate the role of CRIP1 for hypertension-induced vascular inflammation and early medial remodelling in a murine hypertensive model.

METHODS:
Hypertension was induced in Crip1-deficient and C57BL/6 wild-type mice by continuous subcutaneous infusion of angiotensin II (1000 ng/kg/min) for 3 or 7 days using osmotic minipumps. Gene expression in thoracic aorta, heart, and kidney was analyzed by qPCR. Vascular remodelling was evaluated on Elastica Van Gieson stained aortic sections by AI-assisted morphometry. Statistical analysis used two-way ANOVA and unpaired t-tests.

RESULTS:
In WT mice, CRIP1 expression was significantly upregulated after AngII treatment at day 3 and  this increase was more pronounced on day 7 in thoracic aorta (R²=0,44, p=0.0019), heart (R²=0.37, p=0.0003) and kidney (R²=0.55, p=0.006). In the thoracic aorta of CRIP1 deficient mice (n=7-10) inflammatory markers including F4/80 (ƞ²=0.05, p=0.007), Cd68 (ƞ²=0.03, p=0.03), and Il1b, (ƞ²=0.06, p=0.04) were significantly downregulated at day 7, whereas heart and kidney tissues showed no genotype dependent differences in their inflammatory signatures. In contrast, Ccl2 expression in aortic tissue was significantly increased at day 3 of AngII treatment (n=7-10, ƞ²=0.1, p=0.001) and declined seven days after treatment. The aortic medial area at day 7 was reduced in AngII-treated CRIP1-deficient mice compared to the WT mice (n=6–9; η²=0.06, p=0.0096).

CONCLUSION:
Our results indicate that CRIP1 expression is increased during the early phase of AngII-induced hypertension in aortic, cardiac and renal tissues. CRIP1 deficiency reduces expression of vascular inflammatory markers and limits medial thickening. Notably, aortic inflammation is diminished despite a pronounced, transient increase in Ccl2 expression in Crip1 deficient mice. These findings suggest that CRIP1 plays a role in the early stages of hypertension-associated vascular inflammation and remodelling in the aorta, and identify it as a potential target for limiting inflammation-driven remodelling in the initial stages of hypertension.