Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction.

Yves Lecarpentier,Jean-Louis Hã©Bert,Victor Claes,Guillaume Duthoit

doi:10.3389/fphys.2014.00429

Yves Lecarpentier, Jean-Louis Hã©Bert + Show 2 more

Open Access

https://doi.org/10.3389/fphys.2014.00429

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Abstract

Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta, and gamma) play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs) and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998). PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction, hypertension, diabetes, neurodegenerative diseases, cancer which are often closely inter-related.

Highlights

circadian rhythm (CR) are biological temporal processes that display endogenous, entrainable free-running periods that last approximately 24 h
Activation of the Wnt proteins (Wnts)-beta catenin pathway leads to osteogenesis, not adipogenesis and its inhibition leads to an increase in transcription of Peroxisome proliferator-activated receptor (PPAR) gamma
Suppression of DSP expression responsible for human Arrhythmogenic right ventricular cardiomyopathy (ARVC), leads to nuclear localization of PG and to suppression of canonical Wnt/beta-catenin-Tcf/Lef1 signaling in cultured atrial myocytes and in mouse hearts (Sen-Chowdhry et al, 2005)

Summary

Introduction

CRs are biological temporal processes that display endogenous, entrainable free-running periods that last approximately 24 h. The circadian variation in blood pressure and heart rate is disrupted in Bmal1(-/-) and Clock (mut) mice in which core clock genes are deleted or mutated (Curtis et al, 2007). The hormone-dependent interaction of the nuclear receptor RXR alpha with CLOCK negatively regulates CLOCK: BMAL1-mediated transcriptional activation of clock gene expression in vascular cells.

Results

Conclusion