Abstract 543: Inhibition Of Renin-angiotensin System Failed To Suppress Beta-aminopropionitrile-induced Thoracic Aortopathies In Mice

Abstract

Objective: Cross-linking of elastin and collagen fibers is a vital process in aortic development. Pharmacological inhibition of aortic cross-linking by β-aminopropionitrile (BAPN) leads to thoracic aortopathies, such as thoracic aortic aneurysm and dissection, in mice. Although the renin angiotensin system (RAS) contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the RAS protects against aortopathy formation caused by the impairment of elastin and collagen cross-linking in mice. Approach and Results: Either vehicle or losartan (15 mg/kg/d, AT1 receptor blocker) were administered through osmotic pumps for 4 weeks in male C57BL/6J mice (3-4-weeks-old, n=30/group). BAPN (0.5% wt/vol) was given through drinking water to induce aortopathies. Losartan increased plasma renin concentrations significantly compared to vehicle-infused mice, indicating effective blockade of at1 receptors. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor, we also tested the effects of irbesartan, an insurmountable inhibitor of AT1 receptor blocker, on BAPN-induced aortopathy formation (50 mg/kg/day, diet, n=30/group). Despite the significant increase of plasma renin concentrations, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin receptor blockade. We next inhibited angiotensinogen, the unique substrate for angiotensin II, using an antisense oligonucleotide targeting angiotensinogen (AGT-ASO). AGT-ASO decreased plasma angiotensinogen concentrations, while aortic death and dilatations were not attenuated. Since hepatocytes are the major source of angiotensinogen, BAPN-induced thoracic aortopathy formation was also examined in mice with hepatocyte-specific angiotensinogen deletion. Although plasma angiotensinogen concentrations displayed 90% reduction compared to wild type littermates, aortic rupture and aneurysm formation were not suppressed. Conclusion: Inhibition of the RAS does not attenuate BAPN-induced thoracic aortopathy formation in mice.