Group V secretory phospholipase A2 enhances the progression of angiotensin II-induced abdominal aortic aneurysms but confers protection against angiotensin II-induced cardiac fibrosis in apoE-deficient mice.
Abdominal aortic aneurysms (AAAs) and heart failure are complex life-threatening diseases whose etiology is not completely understood. In this study, we investigated whether deficiency of group V secretory phospholipase A(2) (GV sPLA(2)) protects from experimental AAA. The impact of GV sPLA(2) deficiency on angiotensin (Ang) II-induced cardiac fibrosis was also investigated. Apolipoprotein E (apoE)(-/-) mice and apoE(-/-) mice lacking GV sPLA(2) (GV DKO) were infused with 1000 ng/kg per minute Ang II for up to 28 days. Increases in systolic blood pressure, plasma aldosterone level, and urinary and heart prostanoids were similar in apoE(-/-) and GV DKO mice after Ang II infusion. The incidence of aortic rupture in Ang II-infused GV DKO mice (10%) was significantly reduced compared with apoE(-/-) mice (29.4%). Although the incidence of AAA in GV DKO mice (81.3%) and apoE(-/-) mice (100%) was similar, the mean percentage increase in maximal luminal diameter of abdominal aortas was significantly smaller in GV DKO mice (68.5% ± 7.7%) compared with apoE(-/-) mice (92.6% ± 8.3%). Deficiency of GV sPLA(2) resulted in increased Ang II-induced cardiac fibrosis that was most pronounced in perivascular regions. Perivascular collagen, visualized by picrosirius red staining, was associated with increased TUNEL staining and increased immunopositivity for macrophages and myofibroblasts and nicotinamide adenine dinucleotide phosphate oxidase (NOX)-2 and NOX-4, respectively. Our findings indicate that GV sPLA(2) modulates pathological responses to Ang II, with different outcomes for AAA and cardiac fibrosis.
Endocrinology Division, the Department of Internal Medicine, University of Kentucky, Lexington, USA. bbboya2@uky.edu
Boris B
BB
Boyanovsky
William
W
Bailey
Lauren
L
Dixon
Preetha
P
Shridas
Nancy R
NR
Webb
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D001019:Aortic Rupture / Q000201:enzymology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis; D054505:Group V Phospholipases A2 / Q000172:deficiency / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism
D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; D011453:Prostaglandins; D000804:Angiotensin II; D003094:Collagen; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D054505:Group V Phospholipases A2