Cytosolic Phospholipase A ₂ α Is Critical for Angiotensin II–Induced Hypertension and Associated Cardiovascular Pathophysiology

Abstract

Angiotensin II activates cPLA2α and releases arachidonic acid from tissue phospholipids which mediate or modulate one or more cardiovascular effects of angiotensin II and has been implicated in hypertension. Since 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 p58IPK 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 pro-hypertensive effects and activation of one or more signaling molecules including ERK1/2 and cSrc.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ANG II is a known activator of phospholipase A 2 (PLA 2 ) and arachidonic acid production, resulting in downstream eicosanoid production that can exert pro-or antihypertensive effects. Intriguingly, cPLA 2 ␣-deficient mice are protected from ANG II-induced hypertension and show significant prevention of vascular remodeling (aortic hypertrophy, fibrosis) commensurate with reductions in ERK1/2 and cSrc expression (486). In addition, ANG II infusion increases vascular expression of Ca 2ϩ -independent PLA 2 , iPLA 2 ␤.…”

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

“…Eight micrometer thick cross-sectional slices were cut serially, starting from the basal area of the heart, and mounted on histological slides, then incubated in PBS for 30 min. The slides were stained with dihydroethidium (DHE) for 30 min as previously published (22). Images of the stained slides were obtained immediately using a Leica DMI 4000B microscope (Leica Microsystems Inc., Buffalo Grove, IL) at 200 × magnification with an excitation wavelength of 551 nm.…”

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…Histopathologic and immunohistochemistry analyses of collagen, elastin, and a smooth muscle actin were performed to assess the integrity of extracellular matrix, as described. 19 Tissue sections were also processed to determine the infiltration of CD3 þ T cells and F4/80 þ monocytes/macrophages, as described. 19 Immunohistochemistry analysis was also performed to determine the infiltration of CD62p þ platelets, expression of PDGF-A to -D, PDGFR-b, Itg-a2, and COX-2 (Table 1).…”

“…Masson's trichrome staining (catalog number HT-15; Sigma-Aldrich) for collagen was performed on the aorta sections as per the manufacturer's instructions, with some modifications as previously described. 19 Additionally, elastin staining for the aorta sections was performed by the modified Verhoeffevan Gieson staining method, according to the manufacturer's instructions. Briefly, slides with the aorta sections were airdried and fixed in 10% formalin for 10 minutes, followed by rinsing using deionized distilled water.…”