Date of Award
Doctor of Philosophy (PhD)
Molecular Therapeutics and Cell Signaling
Kafait U. Malik, D.Sc., Ph.D.
Suleiman W. Bahouth, Ph.D. Marshall B. Elam, Ph.D. Aviv I. Hassid, Ph.D. Rennolds S. Ostrom, Ph.D.
Cardiac dysfunction, Cytosolic phospholipase A2, End organ damage, Hypertension
Angiotensin II (Ang II) activates cytosolic phospholipase A2α and releases arachidonic acid (AA) from tissue phospholipids. AA metabolites mediate or modulate one or more renocardiovascular effects of this peptide and have been implicated in hypertension. Since AA release is the rate limiting step in eicosanoid production, it is possible that cPLA2α might play a central role in the development of Ang II-induced hypertension. To test this hypothesis, we investigated the effect of Ang II infusion for 13 days by micro-osmotic pumps (700 ng/kg/min), on systolic blood pressure and associated pathophysiological changes in wild type (cPLA2α+/+) and cPLA2α-/- mice. Ang II infusion increased systolic blood pressure in cPLA2α+/+ but not in cPLA2α-/- mice. Ang II induced increase in systolic blood pressure was also abolished by the AA metabolism inhibitor, 5,8,11,14-eicosatetraenoic acid in cPLA2α+/+ mice. Ang II infusion in cPLA2α+/+ mice increased cardiac and renal cPLA2 activity, resulted in cardiovascular and renal dysfunction, caused cardiovascular remodeling, endothelial dysfunction, increased vascular reactivity and compromised renal hemodynamics in cPLA2α+/+ mice; these changes were diminished in cPLA2α-/- mice. Ang II also increased cardiac and renal infiltration of F4/80+ macrophages and CD3+ T lymphocytes, caused cardiac fibrosis and produced cardiovascular and renal oxidative stress and end organ damage, in cPLA2α+/+ but not cPLA2α-/- mice. Infusion of Ang II increased cardiac ER stress and activity of ERK1/2 and cSrc in cPLA2α+/+, but not cPLA2α-/- mice. These data suggest that Ang II-induced hypertension and associated renocardiovascular pathophysiological changes are mediated by cPLA2α activation, most likely through the release of AA and the generation of pro-hypertensive eicosanoids.
Khan, Nayaab Shehbaz , "Group IV Cytosolic Phospholipase A2α Is Critical for the Development of Angiotensin II-Induced Hypertension and Associated Pathogenesis" (2014). Theses and Dissertations (ETD). Paper 346. http://dx.doi.org/10.21007/etd.cghs.2014.0160.