Peroxisome Proliferator-Activated Receptor β/δ Activation in Adult Hearts Facilitates Mitochondrial Function and Cardiac Performance Under Pressure-Overload Condition

Abstract

Abstract-Peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPAR␤/␦ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPAR␤/␦ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPAR␤/␦ mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPAR␥ coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPAR␤/␦ in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPAR␤/␦ activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions. (Hypertension. 2011;57:223-230.) • Online Data Supplement

PGC-1: The Energetic Regulator in Cardiac Metabolism

“…Cardiac overexpression of PPARα induced by PGC-1 dysregulation causes increased FA uptake and oxidation and concomitantly decreased glucose oxidation, which can lead to spontaneous left ventricular dysfunction and lipotoxic cardiomyopathy (Finck et al, 2002;Park et al, 2005). In contrast to PPARα, cardiac overexpression of PPARβ/δ is relatively protective against lipotoxic cardiomyopathy and myocardial infarction (MI) Liu et al, 2011). The differences i n t h e e f f e c t s o f P PA R α and P PA R β / δ overexpression may result from the failure of PPARβ/δ overexpression to induce FA import genes, such as cluster of differentiation 36 (CD36), thereby preventing the toxic accumulation of intracellular lipids (Burkart et al, 2007).…”

The Ubiquitin-Like SUMO System and Heart Function

“…[70][71][72] Conditional overexpression of PPARβ in adult hearts indicate that PPARβ plays a crucial role for the regulation of mitochondrial biogenesis and the enzymatic antioxidant defense system. [73][74][75] Moreover, PPARβ promotes physiological cardiac remodeling. 76 Based on these findings, PPAR agonists were proposed to be beneficial for treatment of heart failure.…”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…Overexpression of PPARb/d in the skeletal muscle led to increased mitochondrial biogenesis through regulation of PPARb/d target gene PGC-1 [106][107][108][109][110][111]. This enhanced mitochondrial biogenesis and subsequent antioxidant defense has been also described in cultured cardiomyocytes and adult hearts [103,112].…”

“…PPARb/d has been implicated in the regulation of cardiac redox balance through effects on transcriptional regulation of antioxidant enzymes or other effectors that could modulate oxidative stress. Specifically, cardiomyocytes-restricted PPARb/d deletion resulted in increased oxidative stress in the heart, mediated from Cu/Zn-SOD and Mn-SOD downregulation [102], while cardiomyocyte-restricted overexpression of a constitutively active PPARb/d enhanced antioxidant capacity resulting in improved cardiac performance under left ventricular pressure overload [103]. A recent in vitro study demonstrated suppression of ROS generation and oxidative stress in cultured cardiac myocytes treated with a PPARb/d agonist, implicating catalase upregulation [104].…”