Faculty Bibliography
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173
Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms
Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.
PMCID:6914828
PMID: 31920701
ISSN: 1664-042x
CID: 4257682
Bioinformatic analysis of a plakophilin-2-dependent transcription network: implications for the mechanisms of arrhythmogenic right ventricular cardiomyopathy in humans and in boxer dogs
Aims/UNASSIGNED:Previous studies in murine hearts and in cell systems have shown that modifications in the expression or sequence integrity of the desmosomal molecule plakophilin-2 (PKP2) can alter the downstream expression of transcripts necessary for the electrical and mechanical function of the heart. These findings have provided support to mechanistic hypotheses that seek to explain arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans. However, the relation between PKP2 expression and the transcriptome of the human heart remains poorly explored. Furthermore, while a number of studies have documented the clinical similarity between familial ARVC in humans and inheritable ARVC in boxer dogs, there is a puzzling lack of convergence as to the possible genetic causes of disease in one species vs. the other. Methods and results/UNASSIGNED:We implemented bioinformatics analysis tools to explore the relation between the PKP2-dependent murine and human transcriptomes. Our data suggest that genes involved in intracellular calcium regulation, and others involved in intercellular adhesion, form part of a co-ordinated gene network. We further identify PROX1 and PPARA (coding for the proteins Prox1 and PPAR-alpha, respectively) as transcription factors within the same network. Conclusion/UNASSIGNED:On the basis our analysis, we hypothesize that the molecular cascades initiated by the seemingly unrelated genetic mutations in humans and in boxers actually converge downstream into a common pathway. This can explain the similarities in the clinical manifestation of ARVC in humans and in the boxer dogs.
PMID: 30476063
ISSN: 1532-2092
CID: 3500482
Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy
PMID: 29716942
ISSN: 1524-4539
CID: 3057032
Connexins and Disease
Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation. As such, both canonical and noncanonical functions of connexins are fundamental components in the pathophysiology of multiple connexin related disorders, many of them highly debilitating and life threatening. Improved understanding of connexin biology has the potential to advance our understanding of mechanisms, diagnosis, and treatment of disease.
PMID: 28778872
ISSN: 1943-0264
CID: 2656052
Proteinâ»Protein Interactions with Connexin 43: Regulation and Function
Connexins are integral membrane building blocks that form gap junctions, enabling direct cytoplasmic exchange of ions and low-molecular-mass metabolites between adjacent cells. In the heart, gap junctions mediate the propagation of cardiac action potentials and the maintenance of a regular beating rhythm. A number of connexin interacting proteins have been described and are known gap junction regulators either through direct effects (e.g., kinases) or the formation of larger multifunctional complexes (e.g., cytoskeleton scaffold proteins). Most connexin partners can be categorized as either proteins promoting coupling by stimulating forward trafficking and channel opening or inhibiting coupling by inducing channel closure, internalization, and degradation. While some interactions have only been implied through co-localization using immunohistochemistry, others have been confirmed by biophysical methods that allow detection of a direct interaction. Our understanding of these interactions is, by far, most well developed for connexin 43 (Cx43) and the scope of this review is to summarize our current knowledge of their functional and regulatory roles. The significance of these interactions is further exemplified by demonstrating their importance at the intercalated disc, a major hub for Cx43 regulation and Cx43 mediated effects.
PMCID:5983787
PMID: 29748463
ISSN: 1422-0067
CID: 3101262
Cardiac chamber-specific human proteome in health and disease: A first quantitative proteomics study from samples collected in vivo [Meeting Abstract]
Background: Genetic/genomic research has greatly advanced our understanding of heart disease. Yet a comprehensive map of the protein landscape of living human hearts is still lacking. Since cardiac protein degradation progresses rapidly post-mortem, it is essential to limit studies to samples collected from live individuals and immediately process these for data acquisition. Objective: To defne the human cardiac chamber-specifc proteome from samples collected in vivo. Methods: Cardiac biopsies of right atria (RA), left atria (LA) and left ventricle (LV) were collected from seven humans undergoing open chest surgery and analyzed by high-resolution mass spectrometry. Results: We identifed 7314 proteins across cardiac chambers. Proteome-wide analysis revealed hundreds of proteins differentially expressed between RA and LA, and between atria and LV with high statistical signifcance. We found over-representation of: a) fbrosis-related proteins in LA, b) autonomic regulation-related proteins in RA, and c) sarcomeric and intercalated disc proteins in LV. We used our data to advance disease-related leads obtained via genetics/genomics. Specifcally, previous GWA studies identifed six loci associated with mitral valve prolapse (MVP). We queried our dataset for abundance of proteins coded by all genes within those 6 loci, recovering gene candidates for fve of these: two genes previously associated with MVP and four new ones. Separately, we found signifcant chamber-specifc over-representation of disease-causing dilated cardiomyopathy variants in LV, with the corresponding observation that protein abundance in LV is signifcantly higher for high-confdence variants. Conclusion: We present the frst comprehensive atlas of chamber-specifc human cardiac protein expression obtained from samples collected in vivo. We identify hundreds of proteins with chamber-specifc expression; some correspond to known functional characteristics and others to novel chamber-specifc identifers, with potential as drug targets. Our studies offer a crucial link between genomic data and the mechanisms of disease
EMBASE:622470202
ISSN: 1556-3871
CID: 3151292
Localized Myosin II Activity Regulates Assembly and Plasticity of the Axon Initial Segment
The axon initial segment (AIS) is the site of action potential generation and a locus of activity-dependent homeostatic plasticity. A multimeric complex of sodium channels, linked via a cytoskeletal scaffold of ankyrin G and beta IV spectrin to submembranous actin rings, mediates these functions. The mechanisms that specify the AIS complex to the proximal axon and underlie its plasticity remain poorly understood. Here we show phosphorylated myosin light chain (pMLC), an activator of contractile myosin II, is highly enriched in the assembling and mature AIS, where it associates with actin rings. MLC phosphorylation and myosin II contractile activity are required for AIS assembly, and they regulate the distribution of AIS components along the axon. pMLC is rapidly lost during depolarization, destabilizing actin and thereby providing a mechanism for activity-dependent structural plasticity of the AIS. Together, these results identify pMLC/myosin II activity as a common link between AIS assembly and plasticity.
PMCID:5805619
PMID: 29395909
ISSN: 1097-4199
CID: 2947452
Novel Imaging Techniques in Cardiac Ion Channel Researc
Cham, Switzerland : Springer, [2018]
pp. 361-378
ISBN: 9783319778112
CID: 3614282
Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression
Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution.
PMCID:6290386
PMID: 30568602
ISSN: 1664-042x
CID: 3556692
Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes
BACKGROUND/BACKGROUND:Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region-specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure. METHODS AND RESULTS/RESULTS:Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham-operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole-cell sodium current (INa) density was decreased by 30% in TAC versus sham-operated on cardiomyocytes. On macropatch analysis, INa in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter-]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z-groove ratios). Using scanning ion conductance microscopy, cell-attached recordings in LM subdomains revealed decreased INa and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α-tubulin and Glu-tubulin expression). Superresolution microscopy showed reduced average NaV1.5 cluster size at the LM of TAC cells, in line with reduced INa. CONCLUSIONS/CONCLUSIONS:Heart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in NaV1.5 clustering and INa within distinct subcellular microdomains of failing cardiomyocytes.
PMCID:5779058
PMID: 29222390
ISSN: 2047-9980
CID: 2835672
