The PPARγ pathway determines electrophysiological remodelling and arrhythmia risks in DSC2 arrhythmogenic cardiomyopathy

Abstract

Dear Editor, Arrhythmogenic cardiomyopathy (ACM) is a rare, lifethreatening genetic disease frequently associated with mutations in desmosomal genes. 1 Histopathological hallmark includes fibrofatty replacement of myocardial tissue, potentially consisting of cardiomyocytes transdifferentiation into adipocytes. 2 The ACM involves electromechanical disorders and risks of developing arrhythmias and sudden cardiac death. We recently evidenced early electrical modifications of human-induced pluripotent stem cellsderived cardiomyocytes (hiPSC-CM) obtained from an ACM patient with a missense mutation (c.394C>T) in the DSC2 gene encoding desmocollin 2 (DSC2-hiPSC-CMs). These modifications are risk factors for triggering arrhythmias independently of fibrofatty replacement of myocardial tissue. 3 We now show that PPARγ, a master regulator of the cardiomyocytes transdifferentiation into adipocytes, is critical early in the pro-arrhythmogenic pathogenesis in ACM-DSC2-hiPSC-CMs.Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of heart samples revealed a higher PPARγ gene expression level in the ACM-heart bearing the DSC2 mutation than in the control heart (Figure S1). We derived hiPSCs from the same ACM-DSC2 patient, differentiated them into hiPSC-CMs, and cultured them for 60 days as described. 3 We found a similar higher expression of PPARγ and of two pro-adipogenic target genes, perilipin and adiponectin, in DSC2-hiPSC-CMs versus control-hiPSC-CMs (Figure 1A-C). Despite lower expression, the pro-cardiac myosin light chain 2 ventricular (MLC2v) validated the cardiomyocyte phenotype of DSC2-hiPSC-CMs (Figure 1D). To confirm the involvement of PPARγ in the genes switch, we challenged DSC2-hiPSC-CMs with T0070907 (T007), which functions as a transcriptionally corepressor-selective PPARγ inverse agonist. 4 Incubation with T007 (1 μM), for 40 days (D20-D60) during the maturation phase, corrected the expres-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Spironolactone as a Potential New Treatment to Prevent Arrhythmias in Arrhythmogenic Cardiomyopathy Cell Model

“…We observed a difference in the firing of spontaneous APs with an increase in the frequency of APs per time unit between the control hiPSC-CMs (0.33 ± 0.06 Hz) and the ACM-DSC2-hiPSC-CMs (0.51 ± 0.07 Hz) ( Figure 2 A,B). AP duration (APD) at 90% of repolarization (APD 90 ) was shorter in the ACM-DSC2-hiPSC-CMs (224 ± 32 ms) than in the control hiPSC-CMs (432 ± 43 ms) ( Figure 2 C) in line with previous results [ 10 , 20 ]. These alterations were similarly normalized following the acute application of SP or CA.…”

“…Based on the available literature, this finding stimulated our investigation into SP impact at the cardiomyocyte level. To test the hypothesis of a direct effect of aldosterone antagonists in ACM patients experiencing arrhythmias, we used hiPSC-CMs obtained from an ACM patient affected by a missense variant (c.394C>T) in the DSC2 gene encoding desmocollin 2 (DSC2-hiPSC-CMs) [ 10 , 20 ].…”

“…In fact, previous studies have suggested that the origin of arrhythmia in ACM is not exclusively due to morphological remodeling [ 4 , 21 ]. The myogenic origin of electrical instability was recently suggested in ACM-DSC2-derived hiPSC-CMs with alterations of both Na + and K + currents, as well as Ca 2+ dynamics [ 10 , 20 ]. In this model, profound electrophysiological remodeling with a critical APD shortening reflects a large increase in repolarizing K + currents.…”

Arrhythmogenic cardiomyopathy as a myogenic disease: highlights from cardiomyocytes derived from human induced pluripotent stem cells

“…Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM. Another study defines the role of PPARγ signaling in electrophysiological and calcium disturbances in ACM hiPSC-CMs and the inhibition of this pathway can rescue these troubles ( Reisqs et al, 2022 ). A very recent publication demonstrates the beneficial effect of spironolactone, an anti-diuretic, to prevent the onset of arrhythmias ( Reisqs et al, 2023 ).…”

Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes

“…PKP2, which is encoded by PKP2 , is a desmosomal protein localized to the outer dense plaque and functions as a scaffold for the other desmosome proteins DSG2, DSC2, JUP, and DSP[ 23 , 36 ] (Figure 1 ). Among the desmosomal genes, mutations in PKP2 are most frequently identified in patients with AC[ 11 , 37 - 39 ], and have been extensively studied using patient-derived iPSC-CMs compared to other desmosomal genes ( DSG2 [ 30 , 40 , 41 ], DSP [ 42 , 43 ], and DSC2 [ 44 , 45 ]). Various clinical phenotypes and pathological characteristics observed in patients with AC harboring PKP2 mutations, downregulated desmosomal protein expression, upregulated lipogenesis, and increased apoptosis in heart tissues have been recapitulated using genetically engineered mouse models[ 11 ] and human cardiomyocytes differentiated from iPSCs[ 46 - 54 ] (Table 1 ).…”