Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression

Gacita, Anthony; Fullenkamp, Dominic E; Ohiri, Joyce C.; Pottinger, Tess D.; Puckelwartz, Megan J.; Nóbrega, Marcelo A.; McNally, Elizabeth M.

doi:10.1161/circulationaha.120.050432

Cited by 39 publications

(40 citation statements)

References 57 publications

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“…To improve variability in iPSC-CM differentiation, we employed a two-step iPSC-CM enrichment ( Figure 2A ). iPSCs were initially differentiated into iPSC-CMs by conventional methods (35,36), followed by a second step in which iPSC-CMs were enriched using a magnetic separation system. Assessment, pre- and post-enrichment by magnetic separation confirmed improved cardiac troponin T positivity ( Figure 2B and 2C ).…”

Section: Resultsmentioning

confidence: 99%

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Recombinant annexin A6 promotes membrane repair in a stem cell derived-cardiomyocyte model of dystrophic cardiomyopathy

Fullenkamp

Willis

Curtin

et al. 2022

Preprint

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Heart failure is a major source of mortality in Duchenne muscular dystrophy (DMD). DMD arises from mutations that ablate expression of the protein dystrophin, which render the plasma membrane unusually fragile and prone to disruption. In DMD patients, repeated mechanical stress leads to membrane damage and cardiomyocyte loss. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer the opportunity to study specific mutations in the context of a human cell, but these models can be improved by adding physiologic stressors. We modeled the primary defect underlying DMD by applying equibiaxial mechanical strain to DMD iPSC-CMs. DMD iPSC-CMs demonstrated an increased susceptibility to equibiaxial strain after 2 hours at 10% strain relative to healthy control cells, measured as increased lactate dehydrogenase (LDH) release. After 24 hours, both DMD and healthy control iPSC-CMs showed evidence of injury with release of LDH and cardiac troponin T. We exposed iPSC-CMs to recombinant annexin A6, a protein resealing agent, and found reduced LDH and troponin release in DMD and control iPSC-CMs that had been subjected to 24 hour strain at 10%. We used aptamer protein profiling of media collected from DMD and control iPSC-CMs and compared these results to serum protein profiling from DMD patients. We found a strong correlation between the proteins in DMD patient serum and media from DMD iPSC-CMs subjected to mechanical stress. By developing an injury assay that specifically targets an underlying mechanism of injury seen in DMD-related cardiomyopathy, we demonstrated the potential therapeutic efficacy of the protein membrane resealer, recombinant annexin A6, for the treatment of DMD-related cardiomyopathy and general cardiac injury.

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Section: Resultsmentioning

confidence: 99%

“…The control line iPSC line (GM033488) was previously described (35). iPSC culture and differentiation were performed per previously published methods (35,36).…”

Section: Methodsmentioning

confidence: 99%

Recombinant annexin A6 promotes membrane repair in a stem cell derived-cardiomyocyte model of dystrophic cardiomyopathy

Fullenkamp

Willis

Curtin

et al. 2022

Preprint

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“…The two cardiac myosin isoforms in an adult human heart are the fast α-myosin (MYH6), which is predominant in the atria, and the slow and more energy-efficient β-myosin, which is expressed primarily in the ventricles [228,229]. The ratio between these two isoforms in the ventricle (α/β: ~1:10) has been implied to be crucial for optimal function [230][231][232][233]. Of particular interest in this regard is the difference between the endocardial and epicardial layers of the ventricle [206] with normally higher α-myosin expression levels in epicardial fibers (Figure 7A).…”

Section: Possible Reasons For Non-uniformities Other Than Varied Expr...mentioning

confidence: 99%

Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

Ušaj¹,

Moretto²,

Månsson³

2022

IJMS

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Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.

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“…Notably, humans display an entirely distinct myosin expression pattern. MHY7 is the major left ventricular MHC in the adults, whereas MYH6 eocodes the myosin enriched in developing human ventricle and adult atrium ( 29 ). Owing to the expression pattern of their host genes, expression of miR-208 family members in adult human hearts showed prominent chamber specificity.…”

Section: Expression Of Mir-208a and Its Regulationmentioning

confidence: 99%

miR-208a in Cardiac Hypertrophy and Remodeling

Huang

et al. 2021

Front. Cardiovasc. Med.

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Various stresses, including pressure overload and myocardial stretch, can trigger cardiac remodeling and result in heart diseases. The disorders are associated with high risk of morbidity and mortality and are among the major health problems in the world. MicroRNAs, a class of ~22nt-long small non-coding RNAs, have been found to participate in regulating heart development and function. One of them, miR-208a, a cardiac-specific microRNA, plays key role(s) in modulating gene expression in the heart, and is involved in a broad array of processes in cardiac pathogenesis. Genetic deletion or pharmacological inhibition of miR-208a in rodents attenuated stress-induced cardiac hypertrophy and remodeling. Transgenic expression of miR-208a in the heart was sufficient to cause hypertrophic growth of cardiomyocytes. miR-208a is also a key regulator of cardiac conduction system, either deletion or transgenic expression of miR-208a disturbed heart electrophysiology and could induce arrhythmias. In addition, miR-208a appeared to assist in regulating the expression of fast- and slow-twitch myofiber genes in the heart. Notably, this heart-specific miRNA could also modulate the “endocrine” function of cardiac muscle and govern the systemic energy homeostasis in the whole body. Despite of the critical roles, the underlying regulatory networks involving miR-208a are still elusive. Here, we summarize the progress made in understanding the function and mechanisms of this important miRNA in the heart, and propose several topics to be resolved as well as the hypothetical answers. We speculate that miR-208a may play diverse and even opposite roles by being involved in distinct molecular networks depending on the contexts. A deeper understanding of the precise mechanisms of its action under the conditions of cardiac homeostasis and diseases is needed. The clinical implications of miR-208a are also discussed.

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Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression

Cited by 39 publications

References 57 publications

Recombinant annexin A6 promotes membrane repair in a stem cell derived-cardiomyocyte model of dystrophic cardiomyopathy

Recombinant annexin A6 promotes membrane repair in a stem cell derived-cardiomyocyte model of dystrophic cardiomyopathy

Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy

miR-208a in Cardiac Hypertrophy and Remodeling

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