Phosphodiesterase Inhibition on Aortic Dissection

Aortic Dissection (AoD) is the disruption in the structural layers of the aortic wall with bleeding into the medial layers. Some of the morbid consequences of AD are free rupture of the aortic wall, or aneurysmal degeneration. AoD has genetic and comorbid risk factors, but many AoD are sporadic in nature. Observations of AoD in laboratory animals and human tissue have revealed excessive smooth muscle cell (SMC) loss, extra- cellular matrix (ECM) degradation and inflammation. There is not a pharmacological or therapeutic agent to decrease the risk of AoD in high risk patients or to promote positive remodeling of the aorta after AoD. Our aim is to investigate mechanisms and therapeutic targets of AoD in a mouse model. A lysyl oxidase inhibitor, 3-aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice. BAPN is administered in the drinking water of 3-week-old mice for 12 weeks induces aortic pathology in 80% of mice. AngII infusion causes even higher incidence of AoD and death. Cilostazol is a phosphodiesterase inhibitor (PDEi) with many vasoactive properties. Cilostazol has been shown to decrease AngII associated aortic pathology in abdominal aorta. Perhaps cilostazol will also have the same attenuation of aortic pathology for the BAPN-induced AoD. Sildenafil is also a PDEi which conversely has been found to induce aortic dissection in a handful of human cases. By studying the possibly different effects of both of the PDEi’s on BAPN-induced AoD, we hope to gain some mechanistic insight to the pathogenesis of AoD.