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

Abstract

Abstract-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), shamϩvehicle, shamϩLA419, clipϩvehicle, and clipϩLA419 (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 (4.10Ϯ0.28 and 3.38Ϯ0.06 mg/g in clipϩvehicle versus clipϩLA419; PϽ0.001) and left ventricular diameter (11.96Ϯ0.25 and 9.90Ϯ0.20 mm in clipϩvehicle versus clipϩLA419; PϽ0.001) 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 Ⅲ NO Ⅲ eNOS Ⅲ Hsp90 Ⅲ cGMP Ⅲ caveolin-3 L eft ventricular (LV) hypertrophy (LVH) is a strong independent predictor of cardiovascular events. Patients with LVH have an increased risk of stroke, coronary heart disease, congestive heart failure, and sudden cardiac death. 1,2 LVH is usually considered to be initially adaptive by normalizing wall stress. However, chronic pressure overload leads eventually to contractile depression, ventricular dilatation, interstitial cardiac fibrosis, and the development of heart failure. 3,4 The mechanisms involved in LVH development and its transition to heart failure are undoubtedly multifactorial and are the subject of intense investigation.A reduced endogenous NO production has been described in many cardiovascular disorders, including cardiac hypertrophy and heart failure. 5 Moreover, it has been demonstrated that both exogenous NO administration and endogenous NO production are able to prevent cardiac hypertrophy development. 6,7 In addition, patients with severe pressure-overload hypertrophy showed marked improvement in diastolic function after acute administration of classical NO donors, 8 and an increase in LV function has been demonstrated recently using low doses of the N...

Melatonin prevents fibrosis but not hypertrophy development in the left ventricle of NG-nitro-L-arginine-methyl ester hypertensive rats

“…Some studies have suggested that NO delivery might attenuate LVH independently of blood pressure reduction [24], whereas others have indicated that the haemodynamic load may be the major determinant of LVH, and neurohumoral activation including NO may play a rather modulatory role [13,25]. The failure of melatonin to affect NOS activity and the insufficient reduction of high blood pressure could partly explain its inability to affect LVH in our study.…”

Sustained Epac activation induces calmodulin dependent positive inotropic effect in adult cardiomyocytes

“…Ventricular cardiomyocytes from male Wistar rats (250-300 g) were isolated using a standard enzymatic digestion as previously described [14,15]. For heart removal, rats were deeply anesthetized with 100 mg/kg sodium pentobarbital.…”

Genistein Prevents Myocardial Hypertrophy in 2-Kidney 1-Clip Renal Hypertensive Rats by Restoring eNOS Pathway

“…For example, chronic treatment with L -NAME, an inhibitor of NO synthesis, can induce cardiac hypertrophy and remodeling independently of the levels of arterial blood pressure [3] . LA419, an NO donor, can prevent dilated cardiac hypertrophy via the eNOS pathway without modifying high arterial blood pressure in a pressure-overloaded animal model [7] . The activated renin-angiotensin system is a major contributor to LVH in a renal hypertensive model [16] .…”

“…Histological examination was studied as described in detail previously [7] . Briefly, excised hearts were perfused with physiological saline solution containing 4% polyformaldehyde solution via retrograde infusion into the ascending aorta at a pressure of 90 mm Hg.…”

“…The critical feature of this rat model lacking NO synthesis is persistent activation of the renin-angiotensin system, which finally leads to myocardial remodeling [6] . More recently, LA419, an NO donor, has been demonstrated to prevent dilated cardiac hypertrophy and myocardial fibrosis via the eNOS pathway without modifying high arterial blood pressure in aortic-stenosed overloaded rats [7] . Cardiomyocyte-restricted overexpression of eNOS is also reported to limit left ventricular dysfunction and remodeling and to abate myocyte hypertrophy in noninfarcted myocardium [8] .…”