4260Loss of Pnn in cardiomyocytes results in impairment of intercalated discs and arrhythmogenic cardiomyopathy in mice

Abstract Background Pnn, a multiple functional protein that localizes within nucleus and in the cytoplasmic region of desmosome. Although recent studies have characterized the physiological role of nuclear Pnn in regulating pre-mRNA alternative splicing and gene transcription, the function of Pnn in desmosome, particularly in cardiomyocytes, remains unidentified. Purpose and methods In the present study, we applied an inducible cardiomyocyte-specific Pnn depletion mouse model (Myh6-CreERT2, Pnnflox/flox) to observe the impact of loss of Pnn on cardiac structure and function in adult mice. Results Six weeks after tamoxifen injection to induce cardiac Pnn depletion, the electrocardiographic abnormalities and decrease of left ventricular ejection fraction (LVEF) were observed. Histopathological examination showed that the proliferation of cardiac fibroblasts and expression of α-smooth muscle actin were increased with Pnn depletion, while the cell-cell connection among cardiomyocytes were impaired. In addition, cellular hypertrophy and decrease of capillary density were also found. Results from Immunofluorescent staining further showed that the distribution pattern of desmosomal proteins and adherent junctional proteins, including desmoglein, desmocollin, plakoglobin, plakophllin, desmoplakin and β-catenin were altered in the cardiomyocytes with Pnn depletion. Both desmosomal and adherent junctional proteins were translocated form cell-cell junction to cytoplasm, indicating the disruption of intercalated discs in Pnn-depleted cardiomyocytes. Microarray data also indicated that loss of cardiac Pnn regulated the mRNA expression of genes responsible for extracellular matrix-receptor interaction, ribosome, and integrin. In addition, expression levels of oxidative stress-associated proteins were significantly regulated by Pnn depletion. Impairment of intercalated disc Conclusion Results from present study indicated that Pnn plays an essential role in the maintenance of intercalated disc integrity of cardiomyocytes, while cardiomyocyte-specific loss of Pnn leads to arrhythmogenic cardiomyopathy in mice. Acknowledgement/Funding Ministry of Science and Technology Taiwan, MOST-106-2320-B-182A-010-MY3