Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C013

Oral Communications

Anti-inflammatory factor Del-1 protects from angiotensin II-induced hypertension and cardiovascular remodelling

I. Kopaliani1, T. Failer1, A. Neuwirth2, G. Hajishengallis3, T. Chavakis2, A. Deussen1

1. Institute of Physiology, Technische Universität Dresden, Dresden, Germany. 2. Universitätsklinik Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany. 3. Penn Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.

Hypertension and cardiovascular diseases are the leading causes of mortality worldwide. Angiotensin II (ANGII), T-cell inflammation, along with TGF-β1 and interleukin 17 (IL-17) have been implicated as key factors in the pathophysiology of hypertension and cardiovascular diseases. Therefore, anti-inflammatory approaches have been proposed as a potential therapeutic strategy. We tested the role of an endogenous anti-inflammatory factor, developmental endothelial locus-1 (Del-1), in prevention of ANGII-induced hypertension and cardiovascular remodeling. Transgenic mice overexpressing endothelial Del-1 (Del1 Tg) and an interventional study in WT mice repetitively injected with soluble Del-1 (50 µg) were used. Hypertension and cardiovascular remodeling was induced via ANGII infusion using osmotic minipumps (4-weeks, Alzet®), implanted under anesthesia with 3% isoflurane. Systolic blood pressure (SBP) was measured via tail-cuff. Mice were sacrificed with a Ketamine overdose (90 mg/kg plus 10 mg/kg Xylazine) and cardiac remodeling was evaluated by histology, whereas flow cytometry for quantification of inflammatory cells and Mulvany myograph for assessment of endothelial function. After 4-weeks of ANGII infusion, Del-1 Tg mice had significantly (P<0.01) lower SBP compared to WT littermates. Left ventricular lumen-to-wall ratio was significantly higher (P<0.01) and cardiomyocyte area smaller (P<0.01) in Del-1 Tg mice compared to WT. Interstitial and perivascular coronary collagen area was significantly (P<0.01) less in Del-1 Tg mice than in WT. Del-1 Tg mice had significantly (P<0.01) less aortic medial thickness, less adventitial collagen (P<0.01) and more elastin (P<0.01) area compared to WT mice. Endothelium-dependent relaxation of aorta was significantly (P<0.01) stronger in Del-1 Tg mice than in WT. Injections of soluble Del-1 completely protected from ANGII-dependent development of hypertension and cardiovascular remodeling. Del-1 injected mice had significantly lower (P<0.05) SBP compared to vehicle treated mice. Del-1 injections resulted in higher (P<0.05) left ventricular lumen-to-wall ratio, lower cardiomyocyte area and less interstitial fibrosis. Del-1 injections also resulted in less aortic medial thickness and adventitial collagen area (P<0.05). Endothelium-dependent relaxation was significantly (P<0.01) better preserved in Del-1 injected mice. Both Del-1 Tg and soluble Del-1 injected mice had less (P<0.05) CD45+ leukocytes, CD3+ T-cells, as well as CD4+ T-helper and CD8+ T-cytotoxic cells, as well as less (P<0.01) active MMP2 and TGF-β1 in heart and aorta compared to WT mice. CD3+/IL-17+ double positive T-cell count was also significantly (P<0.05) less in Del-1 Tg than in WT mice. Our findings demonstrate that Del-1 protects from ANGII-induced hypertension and cardiovascular remodeling via limitation of inflammation and MMP2/TGF-β1 activation. Its proof of efficacy via exogenous injections presents Del-1 as a potential therapeutic agent.

Where applicable, experiments conform with Society ethical requirements