Atorvastatin improves peroxisome proliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappa B activation

Nuclear factor (NF)-kappa B signaling pathway plays a pivotal role in cardiac hypertrophy. Although it has been reported that statins inhibit cardiac hypertrophy by reducing generation of reactive oxygen species, it is not yet known whether statins prevent NF-kappa B activation and whether this effect can be related to the reduction in the peroxisome proliferator-activated receptor (PPAR) pathway. In this study, we examined the role of atorvastatin on NF-kappa B activity and PPAR signaling in pressure overload-induced cardiac hypertrophy. Our findings indicate that atorvastatin inhibits cardiac hypertrophy and prevents the fall in the protein levels of PPAR alpha and PPAR beta/delta. Further, atorvastatin treatment avoided NF-kappa B activation during cardiac hypertrophy, reducing the protein-protein association between these PPAR subtypes and the p65 subunit of NF-kappa B. These findings indicate that negative cross-talk between NF-kappa B and PPARs may interfere with the transactivation capacity of the latter, leading to a fall in the expression of genes involved in fatty acid metabolism, and that these changes are prevented by statin treatment.     

High fat diet induced diabetic cardiomyopathy

In response to a chronic high plasma concentration of long-chain fatty acids (FAs), the heart is forced to increase the uptake of FA at the cost of glucose. This switch in metabolic substrate uptake is accompanied by an increased presence of the FA transporter CD36 at the cardiac plasma membrane and over time results in the development of cardiac insulin resistance and ultimately diabetic cardiomyopathy. FA can interact with peroxisome proliferator-activated receptors (PPARs), which induce upregulation of the expression of enzymes necessary for their disposal through mitochondrial β-oxidation, but also stimulate FA uptake. This then leads to a further increase in FA concentration in the cytoplasm of cardiomyocytes. These metabolic changes are supposed to play an important role in the development of cardiomyopathy. Although the onset of this pathology is an increased FA utilization by the heart, the subsequent lipid overload results in an increased production of reactive oxygen species (ROS) and accumulation of lipid intermediates such as diacylglycerols (DAG) and ceramide. These compounds have a profound impact on signaling pathways, in particular insulin signaling. Over time the metabolic changes will introduce structural changes that affect cardiac contractile characteristics. The present mini-review will focus on the lipid-induced changes that link metabolic perturbation, characteristic for type 2 diabetes, with cardiac remodeling and dysfunction.     

Suppression of cardiac myocyte hypertrophy by conjugated linoleic acid: role of peroxisome proliferator-activated receptors alpha and gamma

Conjugated linoleic acid (CLA) refers to a naturally occurring mixture of positional and geometric isomers of linoleic acid. Evidence suggests that CLA is a dietary constituent and nutraceutical with anti-cancer, insulin-sensitizing, immunomodulatory, weight-partitioning, and cardioprotective properties. The aim of this study was to evaluate the effects of intervention with CLA on cardiac hypertrophy. In vitro, CLA prevented indicators of cardiomyocyte hypertrophy elicited by endothelin-1, including cell size augmentation, protein synthesis, and fetal gene activation. Similar anti-hypertrophic effects of CLA were observed in hypertrophy induced by angiotensin II, fibroblast growth factor, and mechanical strain. CLA may inhibit hypertrophy through activation of peroxisome proliferator-activated receptors (PPARs). CLA stimulated PPAR activity in cardiomyocytes, and the anti-hypertrophic effects of CLA were blocked by genetic and pharmacological inhibitors of PPAR isoforms alpha and gamma. CLA may disrupt hypertrophic signaling by stimulating diacylglycerol kinase zeta, which decreases availability of diacylglycerol and thereby inhibits the protein kinase Cepsilon pathway. In vivo, dietary CLA supplementation significantly reduced blood pressure and cardiac hypertrophy in spontaneously hypertensive heart failure rats. These data suggest that dietary supplementation with CLA may be a viable strategy to prevent pathological cardiac hypertrophy, a major risk factor for heart failure.     

Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes

Peroxisome proliferator-activated receptors (PPARs) (alpha, beta/delta and gamma) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are also very important pharmaceutical targets, and specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders. In particular, compounds of the class of the thiazolinediones (TZDs) are PPARgamma agonists and potent insulin-sensitizers. The specific but still broad expression patterns of PPARgamma, as well as its implication in numerous pathways, constitutes also a disadvantage regarding drug administration, since this potentially increases the chance to generate side-effects through the activation of the receptor in tissues or cells not affected by the disease. Actually, numerous side effects associated with the administration of TZDs have been reported. Today, a new generation of PPARgamma modulators is being actively developed to activate the receptor more specifically, in a cell and time-dependent manner, in order to induce a specific subset of target genes only and modulate a restricted number of metabolic pathways. We will discuss here why and how the development of such selective PPARgamma modulators is possible, and summarize the results obtained with the published molecules.     

Temporal relation of cardiac hypertrophy, oxidative stress, and fatty acid metabolism in spontaneously hypertensive rat

Left ventricular hypertrophy is an adaptive response to hypertension, and an independent clinical risk factor for cardiac failure, sudden death, and myocardial infarction. As regression of cardiac hypertrophy is associated with a lower likelihood of cardiovascular events, it is recognized as a target of antihypertensive therapy. This necessitates identification of factors associated with the initiation and progression of hypertrophy. Oxidative stress and metabolic shift are intimately linked with myocardial hypertrophy, but their interrelationship is not clearly understood. This study proposes to identify the temporal sequence of events so as to distinguish whether oxidative stress and metabolic shift are a cause or consequence of hypertrophy. Spontaneously hypertensive rat (SHR) was used as the experimental model. Cardiac hypertrophy was apparent at 2 months of age, as assessed by hypertrophy index and brain natriuretic peptide gene expression. Enhanced myocardial lipid peroxidation accompanied by nuclear factor-kappa B gene expression in one-month-old SHR suggests that oxidative stress precedes the development of hypertrophy. Metabolic shift identified by reduction in the expression of peroxisome proliferator-activated receptor-alpha, medium chain acyl CoA dehydrogenase, and carnitine palmitoyltransferase 1β was seen at 4 months of age, implying that reduction of fatty acid oxidation is a consequence of hypertrophy. Information on the temporal sequence of events associated with hypertrophy will help in the prevention and reversal of cardiac remodeling. Investigations aimed at prevention of hypertrophy should address reduction of oxidative stress. Both, oxidative stress and metabolic modulation have to be considered for studies that focus on the regression of hypertrophy.     

Mitochondrial dysfunction by synthetic ligands of peroxisome proliferator activated receptors (PPARs)

PPARs are a class of nuclear receptors involved in lipid and glucidic metabolism, immune regulation and cell differentiation. This spectrum of biological activities stimulated pharmacological research to synthetize different molecules with PPARs binding activity with beneficial therapeutic effects. As a matter of fact, some synthetic PPAR-ligands have been already employed in pharmacotherapy: PPAR-alpha ligands, such as fibrates, are used in hyperlipidemias and thiazolidinediones, mainly PPAR-gamma ligands, are employed as insulin sensitizers. However, both classes of drugs showed pharmacotoxicological profiles which cannot be fully ascribed to activation of their specific receptors and which are causing a growing incidence of dramatic side effects (rhabdomyolysis, acute liver failure, heart failure, etc.). A re-evaluation of the biological activities of PPAR synthetic ligands, in particular of the mitochondrial dysfunction based on a rotenone-like Complex I partial inhibition and of its consequent metabolic adaptations, seems to explain some of the pathophysiologic aspects of PPARs allowing a better definition of the therapeutic properties of the so-called PPAR-ligands.     

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.