The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis.

Retinoic-acid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor subfamily consisting of RORα, RORβ, and RORγ. By binding to the ROR response elements (ROREs) on target gene promoters, RORs regulate a wide variety of cellular processes, including autophagy, mitophagy, oxidative stress, and inflammation. The regulatory roles of RORs are observed in cardiac cells, hepatocytes, pulmonary epithelial cells, renal cells, immune cells, and cancer cells.

Oral hormonal contraceptives and cardiovascular risks in females.

Oral hormonal contraception (OHC) is a widely employed method in females for the prevention of unintended pregnancies, as well as for the treatment of menstrual disorders, endometriosis, and polycystic ovarian syndrome. However, it is believed that with OHCs use, some females may have higher risk of cardiovascular diseases, such as hypertension, diabetes, myocardial infarction, thrombosis, and heart failure. Although such risks are infrequently detected in healthy young females with the use of oral contraceptives, slightly elevated risks of cardiovascular diseases have been observed among reproductive-aged healthy females.

Sex-specific considerations in cardiovascular drug therapy.

Despite major advances in cardiac research over the past three decades, cardiovascular disease (CVD) still remains the leading cause of morbidity and mortality in women and men worldwide. However, a major challenge for health care providers is that the current guidelines for cardiovascular drug therapies do not consider the impact of sex in the development of treatment plan for optimizing therapies for women. Clinical research in recent years suggests significant pharmacological and pharmacokinetic differences between females and males, which have been attributed in part to differences in body composition, plasma protein binding capacity, drug metabolism, and excretion.

DIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia.

Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss recent work showing that Mito-ER proximity is regulated by heterotypic complexes between the F-actin polymerizing protein Diaphanous-1) and the mitochondrial dynamics protein Mitofusin 2, which confers increased susceptibility to ischemia/reperfusion injury.

IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.

Aims: The mitochondrial dynamics protein Mitofusin 2 (MFN2) coordinates critical cellular processes including mitochondrial bioenergetics, quality control, and cell viability. The NF-κB kinase IKKβ suppresses mitochondrial injury in doxorubicin cardiomyopathy, but the underlying mechanism is undefined.

Methods And Results: Herein, we identify a novel signalling axis that functionally connects IKKβ and doxorubicin cardiomyopathy to a mechanism that impinges upon the proteasomal stabilization of MFN2.

Autophagy, Clock Genes, and Cardiovascular Disease.

Circadian rhythms are 24-hour cycles that regulate physical, mental, and behavioural changes of most living organisms. In the heart, circadian rhythms regulate processes such as heart rate, blood pressure, blood coagulability, and vascular tone. However, in addition to regulating physiologic processes, circadian rhythms regulate pathophysiologic processes in the heart.

Ellagic acid inhibits mitochondrial fission protein Drp-1 and cell proliferation in cancer.

Anthracyclines such as doxorubicin (Dox) are widely used to treat a variety of adult and childhood cancers, however, a major limitation to many of these compounds is their propensity for inducing heart failure. A naturally occurring polyphenolic compound such as Ellagic acid (EA) has been shown by our laboratory to mitigate the cardiotoxic effects of Dox, however, the effects of EA on cancer cell viability have not been established. In this study, we explored the effects of EA alone and in combination with Dox on cancer cell viability and tumorigenesis.

Circadian regulation of genetic and hormonal risk factors of cardiovascular disease in women.

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. However, sex differences can impact differently the etiology and outcome of cardiovascular disease when comparing men and women. Women have unique genetic and hormonal risk factors that can be associated with the development of cardiovascular diseases.

Circadian regulated control of myocardial ischemia-reperfusion injury.

Circadian mechanisms have been associated with the pathogenesis of a variety of cardiovascular diseases, including myocardial ischemia-reperfusion injury (I-R). Myocardial ischemia resulting from impaired oxygen delivery to cardiac muscle sets into motion a cascade of cellular events that paradoxically triggers greater cardiac dysfunction upon reinstitution of coronary blood supply, a phenomenon known as I-R. I-R injury has been attributed to a number of cellular defects including increased reactive oxygen species (ROS), increased intracellular calcium and impaired mitochondrial bioenergetics that ultimately lead to cardiac cell death, ventricular remodeling and heart failure.

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.

Background: Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival.

NF-κB p65 Attenuates Cardiomyocyte PGC-1α Expression in Hypoxia.

Hypoxia exerts broad effects on cardiomyocyte function and viability, ranging from altered metabolism and mitochondrial physiology to apoptotic or necrotic cell death. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of cardiomyocyte metabolism and mitochondrial function and is down-regulated in hypoxia; however, the underlying mechanism is incompletely resolved. Using primary rat cardiomyocytes coupled with electrophoretic mobility shift and luciferase assays, we report that hypoxia impaired mitochondrial energetics and resulted in an increase in nuclear localization of the Nuclear Factor-κB (NF-κB) p65 subunit, and the association of p65 with the PGC-1α proximal promoter.

Intersection of autophagy regulation and circadian rhythms in the heart.

Autophagy is a vital cellular mechanism that controls the removal of damaged or dysfunctional cellular components. Autophagy allows the degradation and recycling of damaged proteins and organelles into their basic constituents of amino acids and fatty acids for cellular energy production. Under basal conditions, autophagy is essential for the maintenance of cell homeostasis and function.

Mitochondrial autophagy and cell survival is regulated by the circadian gene in cardiac myocytes during ischemic stress.

Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian gene is critically linked to vital physiological processes including mitochondrial fission, fusion and bioenergetics; however, little is known of how the gene regulates these vital processes in the heart. Herein, we identified a putative circadian CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia.

YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles.