Ameliorative Effect of Combination of Fenofibrate and Rosiglitazone in Pressure Overload-Induced Cardiac Hypertrophy in Rats

Abstract

The present study has been designed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α agonist, rosiglitazone, a PPARγ agonist and the combination of both fenofibrate and rosiglitazone in partial abdominal aortic constriction (PAAC)-induced pathological cardiac hypertrophy in rats. Rats were subjected to PAAC for 4 weeks to produce pathological cardiac hypertrophy. The fenofibrate (3 mg/kg day^–1, p.o.), rosiglitazone (3 mg/kg day^–1, p.o.) and the combination of both fenofibrate (3 mg/kg day^–1, p.o.) and rosiglitazone (3 mg/kg day^–1, p.o.) were administered 3 days before PAAC and continued for 4 weeks after PAAC. The development of cardiac hypertrophy was assessed in terms of measuring ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content and LV collagen content. Further, the collagen accumulation in left ventricle was analyzed using picrosirius red staining. Moreover, the cross-sectional area (CSA) of cardiomyocytes was assessed using hematoxylin and eosin staining and measured using a NIH Scion image analyzer. The PAAC produced cardiac hypertrophy by increasing LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. However, treatment with fenofibrate and rosiglitazone either alone or in combination significantly attenuated PAAC-induced increase in LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. The combination of fenofibrate and rosiglitazone was more effective in attenuating the PAAC-induced cardiac hypertrophy than either drug alone. Thus, it may be concluded that dual activation of PPARα and PPARγ may provide synergistic benefits in preventing the development of pathological cardiac hypertrophy.

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

“…In a model of arterial hypertension (DOCAsalt model), PPARα and PPARγ activation were both able to reduce cardiac fibrosis [14] . Similar effects were also observed in a pressure overload-induced cardiac hypertrophy, induced by partial constriction of the abdominal aorta [15] . In addition, PPARα/γ activation had anti-proliferative effects, antagonized angiotensin II actions in vivo and in vitro, and exerted antioxidant actions in inhibiting generation of reactive oxygen species and activating inflammatory mediators in blood vessels and the heart [16] .…”

Fenofibrate reduces cardiac remodeling and improves cardiac function in a rat model of severe left ventricle volume overload

“…16 On the other hand, other studies have concluded that the effects of fibrate treatment on cardiac hypertrophy were mostly positive. Fenofibrate successfully prevent cardiac hypertrophy in a number of in vivo animal models including: high-fat/high-sucrose dietinduced (Fernandes-Santos et al 2009), aldosterone-induced (Lebrasseur et al 2007), partial abdominal aortic constriction induced (Rose et al 2007) and pressure overloadinduced cardiac hypertrophy (Duhaney et al 2007). Our results suggest at least some beneficial effects by preventing LV dilatation, eccentric remodeling and preserving systolic function despite the absence of a clear anti-hypertrophic effect.…”

“…Fibrates are a class of hypolipemic drugs acting on PPARα activation. They have been shown in models of concentric hypertrophy due to pressure overload to have some anti-hypertrophic effects (Chen et al 2007;Diep et al 2004;Harvey et al 2011;Iglarz et al 2003;Lebrasseur et al 2007;Li et al 2009;Nishida et al 2004;Purushothaman et al 2011;Rose et al 2007). …”

Improvement of myocardial lipid accumulation and prevention of PGC-1α induction by fenofibrate

“…Fenofibrate not only prevents the development of hypertension and hypertensive heart disease (27), but also prevents the progression of cardiac hypertrophy either in the pressure-overloaded rat or in the spontaneously hypertensive rat (28,29). Moreover, fenofibrate was shown to protect the heart from isoproterenol-induced acute myocardial ischemic injury (30).…”