Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin‐Deficient Hearts

Hammers, David W.; Sleeper, Margaret M.; Forbes, Sean C.; Shima, Ai; Walter, Glenn A.; Sweeney, H. Lee

doi:10.1161/jaha.116.003911

Cited by 35 publications

(33 citation statements)

References 60 publications

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“…Unfortunately, cardiac function was not evaluated in this study, as the terminal time points selected for skeletal muscle phenotype were earlier than the typical age of cardiomyopathy onset in both mdx and GRMD models (discussed in ref. 33). Future studies focused on cardiac function are needed to determine if treatment with CAT-1041 or edasalonexent prevents or slows the onset of functional cardiomyopathy in our models of DMD.…”

Section: Discussionmentioning

confidence: 99%

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Hammers¹,

Sleeper

Forbes

et al. 2016

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Hammers¹,

Sleeper

Forbes

et al. 2016

JCI Insight

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“…In addition, it should be noted that the subjects in this study were older, ages 7 to 14, and there is precedence for investigating potential benefits of PDE inhibitors in younger DMD boys in future clinical studies. New evidence just published showed that GRMD dogs treated with tadalafil prior to detectable cardiomyopathy exhibited improved cardiac and skeletal muscle histopathological features, decreased TRPC6 levels, and delayed cardiomyopathy 209 .…”

Section: Phoshodiesterase Inhibitionmentioning

confidence: 99%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

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“…Application of tadalafil in dogs with golden retriever muscular dystrophy delays the onset of dystrophic cardiomyopathy. A study has shown that tadalafil decreased TRPC6 expression levels as well as permeation of Ca 2+ by increasing the overall tyrosine phosphorylation of the channel in heart [103]. T69 phosphorylation of TRPC6 was also reported in vascular smooth muscle cells.…”

Section: Phosphorylation-induced Inhibition Of Trpc6mentioning

confidence: 94%

Post-Translational Modification and Natural Mutation of TRPC Channels

Liu

Yao

Tsang

2020

Cells

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Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca2+ permeability and are activated by a wide spectrum of stimuli. These channels are ubiquitously expressed in different tissues and organs in mammals and exert a variety of physiological functions. Post-translational modifications (PTMs) including phosphorylation, N-glycosylation, disulfide bond formation, ubiquitination, S-nitrosylation, S-glutathionylation, and acetylation play important roles in the modulation of channel gating, subcellular trafficking, protein-protein interaction, recycling, and protein architecture. PTMs also contribute to the polymodal activation of TRPCs and their subtle regulation in diverse physiological contexts and in pathological situations. Owing to their roles in the motor coordination and regulation of kidney podocyte structure, mutations of TRPCs have been implicated in diseases like cerebellar ataxia (moonwalker mice) and focal and segmental glomerulosclerosis (FSGS). The aim of this review is to comprehensively integrate all reported PTMs of TRPCs, to discuss their physiological/pathophysiological roles if available, and to summarize diseases linked to the natural mutations of TRPCs.

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Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin‐Deficient Hearts

Cited by 35 publications

References 60 publications

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Post-Translational Modification and Natural Mutation of TRPC Channels

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