Abstract P253: Angiotensin Converting Enzyme Inhibition vs. Angiotensin II Receptor Blockade in Marfan Mouse: Role of Bradykinin

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2015-09, Vol.66 (suppl_1)
• Main Authors: Gamboa, Jorge L, Hill, Kevin D, Fowler, Susan M, Kon, Valentina, Dietz, Harry C, Brown, Nancy J
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.66.suppl_1.p253

Abstract only Angiotensin receptor blockers (ARB) decrease aortic root aneurysm progression in a mouse model of Marfan syndrome, by interfering with angiotensin II (Ang II) activation of transforming growth factor beta (TGF-β) signaling. Angiotensin converting-enzyme inhibitors (ACEi) decrease the formation of Ang II, but also increase bradykinin (BK) which can activate the TGF-β pathway. We tested the hypothesis that ACEi and ARBs differ in their effect on aortic aneurysm development in Fbn1C1039G/+ mice due to different effects on BK. We compared the effect of 12-week treatment with telmisartan (3 and 24 mg/L), ramipril (30mg/L) or placebo in the presence or absence of the BK B2 receptor antagonist HOE140 (0.1 mg/Kg/day). ARB and ACEi reduced blood pressure similarly. ARB and ACEi reduced aortic root diameter (by 17.3±3% and 19.1±5%) but only ARB prevented elastin disruption (Figures 1A and 1B), decreased mast cell infiltration and P-ERK immunoreactivity in the ascending aorta. HOE-140 alone did not reduce the aortic root diameter but diminished the aortic elastin disruption. In the lung, ARB compared to ACEi treatment, prevented the development of emphysematous changes (Figure 1C), decreased mast cell infiltration (4.87±0.98% vs. 9.12±1.23%, p=0.012), and decreased MMP12 (1.02±0.08 vs. 1.52±0.13 A.U, p=0.002) and MMP9 (1.32±0.08 vs. 1.69±0.11 A.U, p=0.006) activity. HOE-140 alone prevented emphysematous changes and decreased MMP12 activity. Endogenous BK contributes to elastin disruption in the aortic root and lung by promoting activation of P-ERK and increasing MMP12 activity, respectively. Clinical studies are required to compare the efficacy of ACEi and ARB in Marfan syndrome.