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(Hypertension. 2007;50:1049.)
© 2007 American Heart Association, Inc.

Original Articles

LA419, a Novel Nitric Oxide Donor, Prevents Pathological Cardiac Remodeling in Pressure-Overloaded Rats Via Endothelial Nitric Oxide Synthase Pathway Regulation

Gema Ruiz-Hurtado; María Fernández-Velasco; Marisabel Mourelle; Carmen Delgado

From the Consejo Superior de Investigaciones Científicas-Universidad Complutense, (G.R.-H., M.F.-V., C.D.), Institute of Pharmacology and Toxicology, Madrid, Spain; and Lacer S.A. (M.M.), Barcelona, Spain.

Correspondence to Carmen Delgado, Consejo Superior de Investigaciones Científicas-Universidad Complutense, Institute of Pharmacology and Toxicology, 28040 Madrid, Spain. E-mail cdelgado{at}med.ucm.es

Reduced endogenous NO production has been described in cardiovascular disorders as cardiac hypertrophy and heart failure. The therapy with conventional nitrates is limited by their adverse hemodynamic effects and drug tolerance. The novel NO donor LA419 has demonstrated important antithrombotic and anti-ischemic properties without those adverse effects. The aim of this study was to evaluate the effect of LA419 chronic treatment on cardiac hypertrophy development in a progressive model of left ventricular hypertrophy. Rats were randomly divided into 6 groups: sham and clip (euthanized 7 weeks after aortic stenosis), sham+vehicle, sham+LA419, clip+vehicle, and clip+LA419 (euthanized 14 weeks after the surgery and treated with vehicle or 30 mg/kg of LA419 once left ventricular hypertrophy was established). LA419 treatment for 7 weeks induced a marked reduction in the heart:body weight ratio (4.10±0.28 and 3.38±0.06 mg/g in clip+vehicle versus clip+LA419; P<0.001) and left ventricular diameter (11.96±0.25 and 9.90±0.20 mm in clip+vehicle versus clip+LA419; P<0.001) without modifying the high blood pressure observed in stenosed rats. Histological analysis revealed that LA419 attenuated myocardial and perivascular fibrosis observed in rats with pressure overload for 14 weeks. In addition, LA419 treatment restored endothelial NO synthase and caveolin-3 expression levels, enhanced the interaction between endothelial NO synthase and its positive regulator the heat shock protein 90, and re-established the normal cardiac content of cGMP in stenosed rats. Thus, LA419 prevented the progression to maladaptative cardiac hypertrophy in response to prolonged pressure overload through a mechanism that involved the re-establishment of the endothelial NO synthase signaling pathway.

Key Words: cardiac hypertrophy • NO • eNOS • Hsp90 • cGMP • caveolin-3

Related Article:

LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway: NO Donors as a Means of Antiremodeling

Ludovit Paulis and Fedor Simko
Hypertension 2007 50: 1009-1011. [Full Text] [PDF]

This article has been cited by other articles:

				L. Paulis and F. Simko LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway: NO Donors as a Means of Antiremodeling Hypertension, December 1, 2007; 50(6): 1009 - 1011. [Full Text] [PDF]