Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation...

Area of Science:

• Cardiovascular Research
• Genetics and Disease Mechanisms
• Pharmacology

Background:

• Marfan syndrome (MFS) is characterized by progressive aortic aneurysm and dissection, a major cause of mortality.
• Angiotensin II receptor blockers (ARBs) show promise in MFS mouse models but have limited efficacy in human patients.
• Aortic dilation in MFS involves complex signaling pathways including G proteins, β-arrestin, and inflammation via MCP-1/CCR2.

Purpose of the Study:

• To investigate the efficacy of targeting β-arrestin signaling with TRV027 in MFS mouse models.
• To explore the potential additive effects of combining lower-dose losartan with β-arrestin (barbadin) or CCR2 (DMX-200) blockers.
• To determine if complete blockade of angiotensin II type 1 receptor (AT1R) is necessary for inhibiting aneurysm progression in MFS.

Main Methods:

• Administration of TRV027, barbadin, DMX-200, and varying doses of losartan to MFS mouse models.
• Comparison of aortic aneurysm progression rates between treated and untreated MFS mice.
• Statistical analysis to determine the significance of observed effects on aneurysm diameter.

Main Results:

• High-dose losartan (50 mg/kg/day) significantly slowed aneurysm progression in MFS mice (1.73 ± 0.12 mm vs. 1.96 ± 0.08 mm, p=0.0033).
• TRV027 alone, barbadin with low-dose losartan, and DMX-200 with low-dose losartan showed no significant beneficial effects.
• Lower doses of losartan were insufficient to halt aneurysm progression, even when combined with other targeted agents.

Conclusions:

• Losartan effectively inhibits aneurysm formation in MFS mouse models, but only at high dosages.
• Targeting β-arrestin signaling or CCR2 with TRV027, barbadin, or DMX-200 in combination with lower-dose losartan is not effective.
• Complete blockade of AT1R signaling appears crucial for preventing aortic aneurysm progression in MFS.