PGY-7 University of Pittsburgh / UPMC Pittsburgh, Pennsylvania, United States
Disclosure(s):
Kamil W. Nowicki, MD, PhD: No financial relationships to disclose
Introduction: We have previously shown that platelet aggregation and subsequent inflammatory cascade has a role in cerebral aneurysm formation. In this work we aimed to clarify the role of CXCL7, CXCR1 and CXCR2 receptors in cerebral aneurysm progression. We show that treatment with P2Y12 / GPIIb/IIIa antagonists or anti-CXCR1, but not anti-CXCR2 blockers prevents aneurysm formation. Furthermore, we show that blockade of this downstream pathway does not affect platelet thrombotic pathway.
Methods: We induced cerebral aneurysm formation in a previously described intracranial aneurysm model via carotid artery ligation, hypertension, and stereotactic elastase injection in C57BL/6 mice. Semi-quantitative cytokines arrays were used to analyze 96 cytokines in murine cerebral aneurysms. Aneurysm formation was then studied in animals treated with 1:3 DMSO:PBS (control), clopidogrel, anti-CXCL7 antibody or anti-CXCR1/2 small molecule inhibitors with primary activity against CXCR1 or CXCR2. We also performed bleeding time assays and flow cytometry to evaluate platelet function.
Results: Mice treated with clopidogrel develop significantly less aneurysms than controls (18% vs 73%, n=11 and 11 respectively, P=0.03). Cytokine array analysis shows increased expression of CXCL7 in both human and mouse aneurysms. Blockade of platelet aggregation decreases detected CXCL7. Targeting CXCL7-CXCR1/2 axis with anti-CXCL7 antibody decreases aneurysm formation (28% vs 75%, n=7 and 8 respectively, P = 0.046). Targeting CXCR1/CXCR2 receptors with reparixin decreases aneurysm formation (11% vs 73%, n=9 and 11, P = 0.0098). Targeting CXCR2 receptor only with SB225002 appears to decrease aneurysm formation, but is not as robust (25% vs 73%, n=11 vs 4, p=0.11). Blockade of CXCR1/2 or CXCR2-only receptors does not affect the thrombotic pathway.
Conclusion : Targeting platelet CXCL7-CXCR1/2 inflammatory axis prevents murine cerebral aneurysm formation. Blockade of CXCR1/2 receptors is superior to blockade of CXCR2 receptor alone. Blockade of CXCR1 or 2 receptors does not affect the platelet thrombotic activity in contrast to P2Y12 or GPIIb/IIIa antagonists.
