Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

Summary: PICH is a DNA translocase necessary for the resolution of ultrafine anaphase DNA bridges and to ensure the fidelity of chromosomal segregation. Here, we report the generation of an animal model deficient for PICH that allowed us to investigate its physiological relevance. Pich KO mice lose viability during embryonic development due to a global accumulation of DNA damage. However, despite the presence of chromosomal instability, extensive p53 activation, and increased apoptosis throughout the embryo, Pich KO embryos survive until day 12.5 of embryonic development. The absence of p53 failed to improve the viability of the Pich KO embryos, suggesting that the observed developmental defects are not solely due to p53-induced apoptosis. Moreover, Pich-deficient mouse embryonic fibroblasts exhibit chromosomal instability and are resistant to RASV12/E1A-induced transformation. Overall, our data indicate that PICH is essential to preserve chromosomal integrity in rapidly proliferating cells and is therefore critical during embryonic development and tumorigenesis. : Albers et al. show that PICH is essential for mouse embryonic development and that PICH deficiency limits oncogenic-induced cellular transformation. These findings suggest that PICH activity is critical during events requiring rapid cell proliferation such as embryonic development and tumorigenesis. Keywords: Pich, Ercc6l, ultrafine anaphase DNA bridges, UFBs, genomic instability, DNA damage, X chromosome inactivatio

Melusin: A cardioprotective chaperone able to modulate lipid metabolism and ROS production in the heart

Melusin is a small-chaperone protein, selectively expressed in the heart and skeletal muscles. In the heart, melusin plays a broad protective role, protecting cardiomyocytes from apoptotic death and sustaining the compensatory myocardial hypertrophy. We recently demonstrated that melusin is able to regulate the activity of the mitochondrial trifunctional protein (MTP), the protein complex responsible for fatty acids β-oxidation in mitochondria, modulating the cardiac metabolism in physiologic and stressconditions. We analyzed the myocardial metabolism and the redox state of mitochondria in mice null and transgenic for melusin in physiologic condition and under stress, induced by transverse aortic constriction or injection of doxorubicin. Our results suggest that melusin is able to balance the lipid metabolism and the ROS production in the heart, ameliorating the cardiac response to stress stimuli. Further studies may allow to find new therapeutic targets and approaches eligible for the treatment of cardiac diseases

Phosphoinositide 3-Kinase (PI3K(p110 alpha))directly regulates key components of the Z-disc and cardiac structure

Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110 alpha) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110 alpha) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110 alpha) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110 alpha) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110 alpha) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment

Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction

AIMS: Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. METHODS AND RESULTS: Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility. CONCLUSIONS: Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling