Store Operated Calcium Entry in Abdominal Aortic Aneurysm

Background: Abdominal Aortic Aneurysm (AAA) is a focal dilatation of the abdominal aorta that progresses over time and eventually ruptures. Surgery is risky but a medical therapy is lacking. Vascular smooth muscle cells (VSMC) are apoptotic in end-stage AAA. There is evidence that they undergo pathological remodelling in early disease. My novel hypothesis is that reduction of this pathological vascular remodelling will be beneficial. Platelet derived growth factor (PDGF) drives VSMC remodelling through IP3 generation, ER Ca2+ store release and store operated Ca2+ entry (SOCE) via the plasma membrane Orai1 channel. In this thesis I will explore the possibilities of small-molecule Orai1 inhibition to attenuate VSMC remodelling and AAA growth.

Methods & Results: A novel Orai1 blocker, JPIII is used throughout the thesis. Orai1 was functionally expressed in AAA VSMC and could be inhibited by JPIII which had nanomolar potency against SOCE and reduced downstream proliferation, migration and apoptosis. JPIII was also effective in rodent VSMC against SOCE and the downstream NFAT activation and was selective for Orai1 in a Cerep selectivity screen. In vivo, three murine models of AAA were used (AngII, CaCl2 and PPE); VSMC remodelling and Orai1 upregulation assessed histologically were apparent in all three models. JPIII treatment reduced AAA VSMC remodelling (by histology) and AAA lumen dimensions (by histology and in vivo ultrasound). JPIII was also effective against AAA progression in mice with established AAA. No major toxic flags were demonstrated but JPIII was a pan CYP450 inhibitor. It was possible to improve the PK of the molecule without loss of the AAA effect.

Conclusion: These data suggest it is possible to modify the VSMC remodelling response in AAA through Orai1 inhibition with a small molecule blocker with no major off target effects in mice. This is a promising starting point for translational development of a therapy for human patients.