Walk the Line: The Role of Ubiquitin in Regulating Transcription in Myocytes

The ubiquitin-proteasome offers novel targets for potential therapies with their specific activities and tissue localization. Recently, the expansion of our understanding of how ubiquitin ligases (E3s) specifically regulate transcription has demonstrated their roles in skeletal muscle, complementing their roles in protein quality control and protein degradation. This review focuses on skeletal muscle E3s that regulate transcription factors critical to myogenesis and the maintenance of skeletal muscle wasting diseases

Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential

Both the ubiquitin-proteasome system (UPS) and the lysosomal autophagy system have emerged as complementary key players responsible for the turnover of cellular proteins. The regulation of protein turnover is critical to cardiomyocytes as post-mitotic cells with very limited regenerative capacity. In this focused review, we describe the emerging interface between the UPS and autophagy, with E3’s regulating autophagy at two critical points through multiple mechanisms. Moreover, we discuss recent insights in how both the UPS and autophagy can alter metabolism at various levels, to present new ways to think about therapeutically regulating autophagy in a focused manner to optimize disease-specific cardioprotection, without harming the overall homeostasis of protein quality control

The ubiquitin ligase MuRF1 regulates PPARα activity in the heart by enhancing nuclear export via monoubiquitination

The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) α by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARα, but not PPARβ/δ or PPARγ in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARα activity and acyl-carnitine intermediates, while MuRF1−/− hearts exhibited increased PPARα activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARα, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARα, along with three specific lysines (292, 310, 388) required for MuRF1s targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARα, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure

Hold Me Tight: Role of the Heat Shock Protein Family of Chaperones in Cardiac Disease

During the development of cardiac hypertrophy, heart failure, and ischemia reperfusion challenge, the heart accumulates misfolded proteins as a result of cellular stresses.1,–,4 Although the compensatory increases in chaperones/cochaperones work to prevent misfolding, refold denatured proteins, and/or target them for degradation, this system can become overwhelmed, leading to worsening of cardiac function. In fact, recent studies have demonstrated experimentally that increasing the burden of misfolded proteins in the heart can contribute to the development of cardiac dysfunction.5 In this review, we discuss the role of heat shock proteins (HSPs) in common cardiac diseases, including cardiac hypertrophy, heart failure, and ischemia/reperfusion injury. Furthermore, we delineate the many specific mechanisms by which these chaperones, cochaperones, and heat shock factor (HSF) transcription factors have been found to be cardioprotective in experimental models. Lastly, we review recent studies involving drugs that are being developed (and currently used) to increase the expression (and presumably function) of chaperone/cochaperone systems that may be applicable to the treatment of common cardiac diseases and familial cardiac diseases with a pathogenesis that includes a major component of misfolded proteins (eg, desminopathies). There are several general families of molecular chaperones in the cytoplasm of mammalian cells, including HSP90, HSP70, chaperonin containing TCP1 (CCT; also called TCP1-ring complex [TRiC]), and small HSP (sHSP) family proteins (the Figure, A). Members of the HSP90 family of chaperones are the most abundant chaperones located in the cytosol. They form dimers consisting of HSP90α and HSP90β subunits and are inducible with stress, although they also are quite abundant without stress.8,9 HSP90 assists many proteins involved with signal transduction, including >40 kinases and many steroid hormone receptors, with a supporting role in conformational changes involved in ATP hydrolysis.10,11 The HSP70 chaperone family consists of

Cardiac Muscle Ring Finger-1—Friend or Foe?

The ubiquitin proteasome system plays a role in regulating protein activity and is integral to the turnover of damaged and worn proteins. In this review, we discuss the recently described relationship between the ubiquitin proteasome system and the cardiac creatine kinase/phospho-creatine shuttle, an essential component of ATP generation and energy shuttling within the heart. The ubiquitin ligase muscle ring finger-1 (MuRF1) binds creatine kinase, leading to its ubiquitination and possible degradation. MuRF1 may also be integral in the regulation of creatine kinase activity in vivo. Since there is a close relationship between the cardiac creatine kinase/phospho-creatine shuttle activity and heart failure, these findings suggest that MuRF1’s role in protein quality control of creatine kinase may be vital to the regulation and maintenance of cardiac energetics to protect against heart failure

Ernest Everett Just, PhD: Pioneer in Ecological Developmental (Eco-Devo) Biology

Ernest Everett Just, a pioneering American biologist, discovered the fundamental role of the environment in the development of embryos. His work led to the creation of the area of biology known as ecological developmental (Eco-Devo) biology. However, both his work and the context of his scientific contributions are not widely known. His work covered a diversity of fields of biology, including marine biology, cytology, and parthogenesis (asexual reproduction where growth and development of embryos occur without fertilization). His findings provided important concepts in developmental biology that are used to this day. Specifically, he demonstrated the importance of the cellular cytoplasm and ectoplasm, in addition to the nucleus, in determining how development occurs in embryos. His worked was unique for its use of in vivo conditions using a variety of marine organisms. His publications on the “Basic Methods for Experiments on Eggs of Marine Mammals” in 1922 and “The Biology of the Cell Surface” in 1939 are still regarded as two of the most comprehensive reviews in cell biology. In this manuscript we present Dr. Just’s childhood in Charleston, SC, unlikely attendance and success at Dartmouth College, and his groundbreaking work, which was developed at the Marine Biological Laboratory (MBL) at Woods Hole, Europe, and Howard University

Nebulized Delivery of the MAPKAP Kinase 2 Peptide Inhibitor MMI-0100 Protects Against Ischemia-Induced Systolic Dysfunction

Acute myocardial infarction (AMI) results in systolic dysfunction, myocarditis and fibrotic remodeling, which causes irreversible pathological remodeling of the heart. Associated cell death and inflammation cause cytokine release, which activates the p38 MAPK signaling pathway to propagate damaging signals via MAPKAP kinase 2 (MK2). Previously we showed that intraperitoneal injection of a cell permeable peptide inhibitor of MK2, MMI-0100, protects against fibrosis, apoptosis and systolic dysfunction in a mouse model of AMI induced by left-anterior descending coronary artery (LAD) ligation. Here we tested a new route of administration of MMI-0100: inhalation of nebulized peptide. When given within 30 min of AMI and daily for 2 weeks thereafter, both inhaled and injected MMI-0100 improved cardiac function as measured by conscious echocardiography. Limited fibrosis was observed after 2 weeks by Massons trichrome staining, suggesting that MMI-0100 protects the heart prior to the formation of significant fibrosis. These results support a nebulized route of administration of MMI-0100 can protect the myocardium from ischemic damage

The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied

SWI/SNF chromatin-remodeling complexes in cardiovascular development and disease

Our understanding of congenital heart defects has been recently advanced by whole exome sequencing projects, which have identified de novo mutations in many genes encoding epigenetic regulators. Notably, multiple subunits of SWI/SNF chromatin-remodeling complexes have been identified as strong candidates underlying these defects because they physically and functionally interact with cardiogenic transcription factors critical to cardiac development, such as TBX5, GATA-4, and NKX2-5. While these studies indicate a critical role of SWI/SNF complexes in cardiac development and congenital heart disease, many exciting new discoveries have identified their critical role in the adult heart in both physiological and pathological conditions involving multiple cell types in the heart, including cardiomyocytes, vascular endothelial cells, pericytes, and neural crest cells. This review summarizes the role of SWI/SNF chromatinremodeling complexes in cardiac development, congenital heart disease, cardiac hypertrophy, and vascular endothelial cell survival. Although the clinical relevance of SWI/SNF mutations has traditionally been focused primarily on their role in tumor suppression, these recent studies illustrate their critical role in the heart whereby they regulate cell proliferation, differentiation, and apoptosis of cardiac derived cell lines

Corticosteroids Are Essential for Maintaining Cardiovascular Function in Male Mice

Activation of the hypothalamic-pituitary-adrenal axis results in the release of hormones from the adrenal glands, including glucocorticoids and mineralocorticoids. The physiological association between corticosteroids and cardiac disease is becoming increasingly recognized; however, the mechanisms underlying this association are not well understood. To determine the biological effects of corticosteroids on the heart, we investigated the impact of adrenalectomy in C57BL/6 male mice. Animals were adrenalectomized (ADX) at 1 month of age and maintained for 3–6 months after surgery to evaluate the effects of long-term adrenalectomy on cardiac function. Morphological evaluation suggested that ADX mice showed significantly enlarged hearts compared with age-matched intact controls. These changes in morphology correlated with deficits in left ventricular (LV) function and electrocardiogram (ECG) abnormalities in ADX mice. Correlating with these functional defects, gene expression analysis of ADX hearts revealed aberrant expression of a large cohort of genes associated with cardiac hypertrophy and arrhythmia. Combined corticosterone and aldosterone replacement treatment prevented the emergence of cardiac abnormalities in ADX mice, whereas corticosterone replacement prevented the effects of adrenalectomy on LV function but did not block the emergence of ECG alterations. Aldosterone replacement did not preserve the LV function but prevented ECG abnormalities. Together, the data indicate that adrenal glucocorticoids and mineralocorticoids either directly or indirectly have selective effects in the heart and their signaling pathways are essential in maintaining normal cardiac function