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

MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

The cell-permeant peptide inhibitor of MAPKAP kinase 2 (MK2), MMI-0100, inhibits MK2 and downstream fibrosis and inflammation. Recent studies have demonstrated that MMI-0100 reduces intimal hyperplasia in a mouse vein graft model, pulmonary fibrosis in a murine bleomycin-induced model and development of adhesions in conjunction with abdominal surgery. MK2 is critical to the pathogenesis of ischemic heart injury as MK2 −/− mice are resistant to ischemic remodeling. Therefore, we tested the hypothesis that inhibiting MK2 with MMI-0100 would protect the heart after acute myocardial infarction (AMI) in vivo. AMI was induced by placing a permanent LAD coronary ligation. When MMI-0100 peptide was given 30 minutes after permanent LAD coronary artery ligation, the resulting fibrosis was reduced/prevented ~50% at a 2 week time point, with a corresponding improvement in cardiac function and decrease in left ventricular dilation. In cultured cardiomyocytes and fibroblasts, MMI-0100 inhibited MK2 to reduce cardiomyocyte caspase 3/7 activity, while enhancing primary cardiac fibroblast caspase 3/7 activity, which may explain MMI-0100’s salvage of cardiac function and anti-fibrotic effects in vivo. These findings suggest that therapeutic inhibition of MK2 after acute MI, using rationally-designed cell-permeant peptides, inhibits cardiac fibrosis and maintains cardiac function by mechanisms that involve inhibiting cardiomyocyte apoptosis, while enhancing primary cardiac fibroblast cell death

Targeting Angiogenesis and the Tumor Microenvironment

The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Critical elements in the microenvironment include tumor associated fibroblasts, which provide an essential communication network via secretion of growth factors and chemokines, inducing an altered extracellular matrix (ECM), thereby providing additional oncogenic signals that enhance cancer-cell proliferation and invasion. Active contribution of tumor-associated stromal cells to cancer progression has been recognized. Stromal elements consist of the ECM, fibroblasts of various phenotypes, and a scaffold composed of immune and inflammatory cells, blood and lymph vessels, and nerves. This review will focus on therapeutic targets in the microenvironment related to tumor endothelium, tumor associated fibroblasts and the extracellular matrix

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

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

Mitochondria as a Source and Target of Lipid Peroxidation Products in Healthy and Diseased Heart

The heart is a highly oxidative organ in which cardiomyocyte turnover is virtually absent, making it particularly vulnerable to accumulation of lipid peroxidation products (LPP) formed as a result of oxidative damage. Reactive oxygen and nitrogen species are the most common electrophiles formed during lipid peroxidation and lead to the formation of both stable and unstable LPP. Of the LPP formed, highly reactive aldehydes are a well-recognized causative factor in ageing and age-associated diseases, including cardiovascular disease and diabetes. Recent studies have identified that the mitochondria are both a primary source and target of LPP, with specific emphasis on aldehydes in cardiomyocytes and how these affect the electron transport system and Ca(2+) balance. Numerous studies have found that there are functional consequences in the heart following exposure to specific aldehydes (acrolein, trans-2-hexanal, 4-hydroxynonenal and acetaldehyde). Because these LPP are known to form in heart failure, cardiac ischaemia-reperfusion injury and diabetes, they may have an underappreciated role in the pathophysiology of these disease processes. Lipid peroxidation products are involved in the transcriptional regulation of endogenous anti-oxidant systems. Recent evidence demonstrates that transient increases in LPP may be beneficial in cardioprotection by contributing to mitohormesis (i.e. induction of anti-oxidant systems) in cardiomyocytes. Thus, exploitation of the cardioprotective actions of the LPP may represent a novel therapeutic strategy for future treatment of heart disease

The ubiquitin–proteasome system in cardiac dysfunction

Abstract Since proteins play crucial roles in all biological processes, the finely tuned equilibrium between their synthesis and degradation regulates cellular homeostasis. Controlling the quality of proteome informational content is essential for cell survival and function. After initial synthesis, membrane and secretory proteins are modified, folded, and assembled in the endoplasmic reticulum, whereas other proteins are synthesized and processed in the cytosol. Cells have different protein quality control systems, the molecular chaperones, which help protein folding and stabilization, and the ubiquitin–proteasome system (UPS) and lysosomes, which degrade proteins. It has generally been assumed that UPS and lysosomes are regulated independently and serve distinct functions. The UPS degrades both cytosolic, nuclear proteins, and myofibrillar proteins, whereas the lysosomes degrade most membrane and extracellular proteins by endocytosis as well as cytosolic proteins and organelles via autophagy. Over the last two decades, the UPS has been increasingly recognized as a major system in several biological processes including cell proliferation, adaptation to stress and cell death. More recently, activation or impairment of the UPS has been reported in cardiac disease and recent evidence indicate that autophagy is a key mechanism to maintain cardiac structure and function. This review mainly focuses on the UPS and its various components in healthy and diseased heart, but also summarizes recent data suggesting parallel activation of the UPS and autophagy in cardiac disease