Abstract Th0001: Phosphodiesterase 3 or 5 Inhibitors Have No Effect on BAPN-induced Aortic Dissection and Aneurysm

Introduction: Aortic Dissection (AoD) is the disruption in the layers of the aortic wall with bleeding into the medial layers. Aortic Aneurysm (AA) is a dilation of the aorta. One fatal consequence of AoD and AA is the free rupture of the aortic wall. There is no pharmacological or therapeutic agents to decrease the risk of aortic rupture after AoD. Phosphodiesterase inhibitor (PDEi) 3 and 5 have many uses clinically including vasodilatory small and large vessels, as well as anti-platelet activity in peripheral vessels. Two studies suggest protective effects of cilostazol in abdominal aortic aneurysm (AAA), and one study found sildenafil exacerbated AAA. These agents have not been tested directly in a mouse model of thoracic AoD or AA. This is a gap in knowledge. It is unknown if PDEi’s will be efficacious in attenuating AoD or AA.

Methods and Results: A lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), was administered to induce AA and AoD in male C57BL/6J mice at 4 weeks of age. We first performed bulk RNA sequencing using ascending and descending aortas harvested from mice with BAPN administration for 1 week, representing the pre-AoD/AA phase. PDE3 and PDE5 mRNA abundance were significantly increased in both ascending and descending aortas. To determine the impact of pharmacological inhibition of PDE3 and PDE5, either cilostazol (a PDE3 inhibitor) or sildenafil (a PDE5 inhibitor) was administered by diet to BAPN-administered mice for 4 weeks. Mice fed a regular diet were used as controls. Mass spectrometry of plasma samples verified the delivery of cilostazol or sildenafil in mice at 4 weeks of BAPN administration. Despite effective drug delivery, neither cilostazol nor sildenafil affected the incidence of aortic rupture in BAPN-administered mice. In addition, AA formation assessed by the in situ imaging approach was not changed by either drug. Extending the observation period to 12 weeks showed consistent findings, with no significant differences among the groups in the survival rate or aortic diameters in BAPN-treated mice.

Conclusion: Although there is interest on the clinical effect of PDE 3 an 5 inhibitors on anerysm diesease. There is no protective or exacerbating effect of phosphodiesterase inhibitors cilostazol and sildenafil on BAPN-induced AoD and AA in mice. Further work is needed to gain mechanistic insight.