Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure

Abstract

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure. The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.

Novel Anti-fibrotic Therapies

“…In several different models of cardiac fibrosis, fenofibrate prevented interstitial and perivascular cardiac fibrosis, through a mechanism that involved reduced endothelin-1 levels (Ogata et al, 2002, 2004; Iglarz et al, 2003; Diep et al, 2004; LeBrasseur et al, 2007; Forcheron et al, 2009; Zhang et al, 2016). Similar results were observed using inducible overexpression of PPARα early in the progression of pressure overload-induced cardiac damage (Kaimoto et al, 2016). However, one study using fenofibrate treatment of chronic pressure overload in PPARα knockout mice showed that fenofibrate had profibrotic effects that were independent of PPARα (Duhaney et al, 2007).…”

Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart

“…Intensive studies over the past two decades have begun to uncover the staggering complexity of metabolic regulation directed by a plethora of cross-activating transcription factors, including nuclear receptor family members (12,13,(32)(33)(34). Dynamic interactions between these factors orchestrate metabolic remodeling in response to various physiological and pathophysiological stimuli (35)(36)(37)(38)(39)(40). Prominent among these factors is the transcriptional coactivator PGC-1α, which acts as a master regulator of mitochondrial oxidative metabolism by coordinating the capacity of each step required for ATP synthesis (20).…”

Qishen granules exerts cardioprotective effects on rats with heart failure via regulating fatty acid and glucose metabolism

“…Energy metabolism has become the promising therapeutic targets for HF [6]. HF is characterized by dysfunction of generating adenosine triphosphate (ATP) to maintain cardiac contractility due to the metabolic imbalance of fatty acid (FA) and glucose metabolisms [7]. In the healthy circumstances, fatty acid oxidation (FAO) is the major resource of ATP [6].…”