Chymase-independent vascular Ang-(1-12)/Ang II pathway and TXA2 generation are involved in endothelial dysfunction in the murine model of heart failure

The angiotensin (Ang)-(1-12)/Ang II pathway contributes to cardiac pathology. However, its involvement in the development of peripheral endothelial dysfunction associated with heart failure (HF) remains unknown. Therefore, this study aimed to characterise the effect of exogenous Ang-(1-12) and its conversion to Ang II on endothelial function using the murine model of HF (Tg alpha q*44 mice), focusing on the role of chymase and vascular -derived thromboxane A2 (TXA2). Ex vivo myographic assessments of isolated aorta showed impaired endothelium -dependent vasodilation in late -stage HF in 12 -month -old Tg alpha q*44 mice. However, endothelium -dependent vasodilation was fully preserved in the early stage of HF in 4 -month -old Tg alpha q*44 mice and 4- and 12 -month -old FVB control mice. Ang-(1-12) impaired endothelium -dependent vasodilation in 4- and 12 -month -old Tg alpha q*44 mice, that was associated with increased Ang II production. The chymase inhibitor chymostatin did not inhibit this response. Interestingly, TXA2 production reflected by TXB2 measurement was upregulated in response to Ang-(1-12) and Ang II in aortic rings isolated from 12 -month -old Tg alpha q*44 mice but not from 4 -month -old Tg alpha q*44 mice or age -matched FVB mice. Furthermore, in vivo magnetic resonance imaging showed that Ang-(1-12) impaired endothelium -dependent vasodilation in the aorta of Tg alpha q*44 mice and FVB mice. However, this response was inhibited by angiotensin I converting enzyme (ACE) inhibitor; perindopril, angiotensin II receptor type 1 (AT1) antagonist; losartan and TXA2 receptor (TP) antagonist-picotamide in 12-month-old-Tg alpha q*44 mice only. In conclusion, the chymase-independent vascular Ang-(1-12)/Ang II pathway and subsequent TXA2 overactivity contribute to systemic endothelial dysfunction in the late stage of HF in Tg alpha q*44 mice. Therefore, the vascular TXA2 receptor represents a pharmacotherapeutic target to improve peripheral endothelial dysfunction in chronic HF.