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Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A₂ in Young Spontaneously Hypertensive Rats

Scott Levick^*, David Loch^*, Barbara Rolfe, Robert C. Reid, David P. Fairlie, Stephen M. Taylor^* and Lindsay Brown^1,*

^* Department of Physiology and Pharmacology, School of Biomedical Sciences, Centre for Research in Vascular Biology, and Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia

The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A₂ (sPLA₂-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA₂-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 ± 0.9%, n = 5; SHR+KH064 14.0 ± 1.2%, n = 5) and interstitial (SHR 7.9 ± 0.3%, n = 6; SHR+KH064 5.4 ± 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 ± 0.08, n = 12; SHR+KH064 3.09 ± 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA₂-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.

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