title: Cytosolic phospholipase A2α is critical for angiotensin II-induced hypertension and associated cardiovascular pathophysiology.
abstract: Angiotensin II activates cytosolic phospholipase A(2)α (cPLA2α) 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, cPLA2α 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 (cPLA2α(+/+)) and cPLA2α(-/-) mice. Angiotensin II-induced increase in systolic blood pressure in cPLA2α(+/+) mice was abolished in cPLA2α(-/-) mice; increased systolic blood pressure was also abolished by the arachidonic acid metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid in cPLA2α(+/+) mice. Angiotensin II in cPLA2α(+/+) mice increased cardiac cPLA2 activity and urinary eicosanoid excretion, decreased cardiac output, caused cardiovascular remodeling with endothelial dysfunction, and increased vascular reactivity in cPLA2α(+/+) mice; these changes were diminished in cPLA2α(-/-) mice. Angiotensin II also increased cardiac infiltration of F4/80(+) macrophages and CD3(+) T lymphocytes, cardiovascular oxidative stress, expression of endoplasmic reticulum stress markers p58(IPK), and CHOP in cPLA2α(+/+) but not cPLA2α(-/-) mice. Angiotensin II increased cardiac activity of ERK1/2 and cSrc in cPLA2α(+/+) but not cPLA2α(-/-) mice. These data suggest that angiotensin II-induced hypertension and associated cardiovascular pathophysiological changes are mediated by cPLA2α 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.
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Nayaab S
authors: NS
authors: Khan
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Chi Young
authors: CY
authors: Song
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Brett L
authors: BL
authors: Jennings
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Anne M
authors: AM
authors: Estes
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Xiao R
authors: XR
authors: Fang
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.).
authors: Joseph V
authors: JV
authors: Bonventre
authors: From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN (N.S.K., C.Y.S., B.L.J., A.M.E., X.R.F., K.U.M.); and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Institute of Medicine, Boston, MA (J.V.B.). kmalik@uthsc.edu.
authors: Kafait U
authors: KU
authors: Malik
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis / Q000235:genetics*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000804:Angiotensin II; D012313:RNA; D054513:Group IV Phospholipases A2
keywords: angiotensin II; cytosolic phospholipase A2α (cPLA2α); inflammation; mice; oxidative stress