Cytosolic Phospholipase A(2)alpha Is Critical for Angiotensin II-Induced Hypertension and Associated Cardiovascular Pathophysiology

Angiotensin II activates cytosolic phospholipase A(2)alpha (cPLA(2)alpha) and releases arachidonic acid from tissue phospholipids, which mediate or modulate >= 1 cardiovascular effects of angiotensin II and has been implicated in hypertension. Because arachidonic acid release is the rate limiting step in eicosanoid production, cPLA(2)alpha might play a central role in the development of angiotensin II-induced hypertension. To test this hypothesis, we investigated the effect of angiotensin II infusion for 13 days by micro-osmotic pumps on systolic blood pressure and associated pathogenesis in wild type (cPLA(2)alpha(+/+)) and cPLA(2)alpha(-/-) mice. Angiotensin II-induced increase in systolic blood pressure in cPLA(2)alpha(+/+) mice was abolished in cPLA(2)alpha(-/-) mice; increased systolic blood pressure was also abolished by the arachidonic acid metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid in cPLA(2)alpha(+/+) mice. Angiotensin II in cPLA(2)alpha(+/+) mice increased cardiac cPLA(2) activity and urinary eicosanoid excretion, decreased cardiac output, caused cardiovascular remodeling with endothelial dysfunction, and increased vascular reactivity in cPLA(2)alpha(+/+) mice; these changes were diminished in cPLA(2)alpha(-/-) mice. Angiotensin II also increased cardiac infiltration of F4/80(+) macrophages and CD3(+) T lymphocytes, cardiovascular oxidative stress, expression of endoplasmic reticulum stress markers p58IPK, and CHOP in cPLA(2)alpha(+/+) but not cPLA(2)alpha(-/-) mice. Angiotensin II increased cardiac activity of ERK1/2 and cSrc in cPLA(2)alpha(+/+) but not cPLA(2)alpha(-/-) mice. These data suggest that angiotensin II-induced hypertension and associated cardiovascular pathophysiological changes are mediated by cPLA(2)alpha activation, most likely through the release of arachidonic acid and generation of eicosanoids with predominant prohypertensive effects and activation of >= 1 signaling molecules, including ERK1/2 and cSrc.