The function of iASPP in Cardiomyocytes

Introduction: Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. In our recent published work in collaboration with Prof. Tzipora C. Falik-Zaccai, five Arab-Christian-infants, ages 4-30 months from four families were diagnosed with DCM associated with mild skin, teeth and hair abnormalities. All passed away before age 3. A homozygous sequence variation in PPP1R13L encoding the iASPP protein, was identified in three infants, and heterozygous in the mother of the other two. The patients’ fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to Lipopolysaccharide (LPS), as well as ppp1r13l-knocked down murine cardiomyocytes and hearts of ppp1r13l-deficient mice. The hypersensitivity to LPS was NF-κB-dependent, and NF-κB-inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients’ fibroblasts. RNA-sequencing of ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in ppp1r13l-deficient (Wa3) mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Altogether, these results demonstrated PPP1R13L as the gene underlying a novel autosomal recessive cardiocutaneous syndrome (CCS) in humans, and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors. However, the mechanisms underlying the function of iASPP in regulating NF-κB activity and cardiac response are unknown.

Material and method: Heart tissues were purified, and cardiomyocytes were harvested from homozygous BALB/c wa3 mice and their littermate WT mice and were processed for confocal microscopy imaging and molecular assays.

Results and discussion: Our preliminary results suggest that iASPP regulates cellular translocations of NF-κB.