We read with interest the extensive review by Jacoby and Rader1 on the vast subject of the renin-angiotensin system in atherothrombotic disease. A number of closely related points deserve discussion.
First, angiotensin II (AT2) can be cleaved to the hexapeptide angiotensin IV (AT4) as outlined by the authors. However, Jacoby and Rader1 do not point out that plasminogen activator inhibitor-1 (PAI-1) expression is not induced until the octapeptide AT2 is converted to AT4.2 Endothelial PAI-1 expression thus appears to occur via the AT4 receptor, an endothelial receptor specific for AT4. Specific antagonist of the AT2 type-1 receptor (eg, with the angiotensin receptor blocker [ARB] losartan) may therefore have little beneficial or perhaps even an adverse effect (through loss of feedback and increased angiotensin levels3 on the fibrinolytic balance. Indeed, in vivo studies comparing losartan with ACE inhibitors have shown improved fibrinolytic balance (by decreasing circulating concentrations of PAI-1) with the latter but not former.4,5
Lim HS, Lip GYH. Is Angiotensin Receptor Blockade Antithrombotic?. Arch Intern Med. 2003;163(22):2790-2791. doi:10.1001/archinte.163.22.2790-a