Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient–Specific Cardiomyocytes by Immunoproteasome Modulation

Abstract

detection of cardiomyopathy represent the requirements for successful cardioprotective therapies that block or at least slow the processes of cardiac remodeling and heart failure. 3 Unfortunately, the current treatments for dilated cardiomyopathy are still inadequate because a deep understanding of the specific mechanisms underlying DMD-attributable heart failure is A.F. and A.G. contributed equally to this work.

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

“…The nitrogenous bases are incorporated on a morpholine six-membered Golodirsen was developed for the treatment of Duchenne's muscular dystrophy (DMD), which is a progressive muscle deterioration that starts in early childhood and in most cases ends up crippling patients before adolescence. After several years, patients die mainly from heart failure [7,8]. This disorder is caused by a deletion mutation in the dystrophin gene, which transcribes for the production of dystrophin, a huge protein that covers muscular fibers, protecting them from damage upon contraction and enhancing muscle performance.…”

“Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

“…In the last few years, iPSC-CMs have been widely used to model cardiac diseases including DAC, and more than 20 original articles reported the use of iPSC-derived cells from MD patients. Starting from the first iPSC line derived from skin fibroblasts of a DMD patient in 2008 [ 341 ], numerous other iPSC cell lines derived from different somatic-cell sources obtained from DMD and BMD patients were generated and published [ 133 , 253 , 302 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 , 367 , 368 ]. These works demonstrated that it is possible to use iPSC-derived cells carrying specific DMD mutations to reproduce MD pathogenesis and to verify new therapeutic approaches.…”

“…Among them, calcium handling is one of the most studied in iPSC-CMs. Indeed, the use of different DMD iPSC-CMs permitted the demonstration that calcium homeostasis is altered in DMD iPSC-CMs, which showed slower Ca 2+ transients [ 342 ], profound reduction of the L-type calcium current with augmented cytosolic Ca 2+ levels [ 344 ], increased diastolic Ca 2+ levels and Ca 2+ transient amplitudes after a short-term mechanical stretch protocol [ 360 ], augmented intracellular diastolic Ca 2+ levels [ 355 ], slowed Ca 2+ transient rise, and decay compared to controls after field stimulation pacing [ 363 ]. In addition to calcium handling, alterations in iPSC-CM DMD models showed increased levels of ROS [ 366 ], overexpression of immunoproteasome subunits, and increased release of tumor necrosis factor (TNF)-α and cTnI [ 355 ].…”

“…Lin and colleagues demonstrated that treatment with the membrane sealant compound poloxamer 188 significantly decreased resting cytosolic Ca 2+ level, repressed caspase-3 activation, and consequently suppressed apoptosis in DMD iPSC-CMs [ 344 ]. Additionally, the immunoproteasome inhibitor ONX-0914 was shown to improve the health of iPSC-CMs as indicated by reduced sarcolemmal damage and proinflammatory signaling in MD iPSC-CMs treated with ONX-0914 [ 355 ]. In another study, Afzal and collaborators showed that the vasodilator nicorandil protected iPSC-CMs from damage observed as a consequence of DMD mutations, i.e., reduced DNA damage and mitochondrial stress [ 346 ].…”

“…Moreover, in the pathological environment, cFbs are stimulated to differentiate into myofibroblasts that can express smooth-muscle contractile proteins, proliferate rapidly, and secrete significant amounts of ECM leading to cardiac fibrosis. This fibrotic loop is exacerbated by the production of TGF-β, which, as well as being responsible for cardiac hypertrophy by activating the SMAD signaling pathway in iPSC-CMs [ 355 ], also induces epithelial to mesenchymal transformation of endothelial cells into cFbs, thus increasing the pool of cells secreting ECM [ 374 ]. These cell types could play an important role in the development of the DAC.…”