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JCI online ahead of print table of contents for May 1, 2014

Balancing protein turnover in the heart

Alterations in the ubiquitin proteasome system (UPS), which tags proteins for degradation, underlies some cardiomyopathies and age-related cardiac dysfunction. In the heart, the UPS is essential for the precise balance between cardiomyocyte atrophy and hypertrophy. In skeletal muscle, the E3 ubiquitin ligase atrogin-1 promotes atrophy by targeting hypertrophy-associated proteins for degradation; however, a role for atrogin-1 in cardiac proteostasis is not clear. In this issue of the Journal of Clinical Investigation, Marco Sandri, Marco Mongillo and colleagues at the Venetian Institute of Molecular Medicine investigated cardiac homeostasis in atrogin-1-deficient mice. Aged animals lacking atrogin-1 exhibited enlarged and abnormally shaped hearts, thickened left ventricular walls, increased fibrosis and apoptosis, and reduced function. Loss of atrogin-1 led to increased ER stress and upregulation of genes involved in the unfolded protein response (UPR). Moreover, autophagy, which is inhibited by the UPR in skeletal muscle, was also repressed in cardiac tissue of atrogin-1 null animals, suggesting that atrogin-1 may target autophagy-related proteins for degradation. Evaluation of cardiac protein turnover in atrogin-1-deficient animals revealed reduced turnover of lysosomal targets, including the endosomal sorting complex III protein CHMP2B. Silencing CHMP2B in atrogin-1 null mice restored markers of autophagy and reduced apoptosis in the heart. These results indicated that UPS-regulated autophagy in the protein turnover necessary for cardiomyocyte health.

TITLE: Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy

Venetian Institute of Molecular Medicine, Padova, UNK, ITA
Phone: +39 049 7923258; Fax: +39 049 7923250; E-mail:


Marco Mongillo
Venetian Institute of Molecular Medicine, Padova, UNK, ITA
Phone: 390497923229; Fax: 390497923250, E-mail: marco.mongillo@unipd.i

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Protecting the kidney from hypoxia-induced damage

Acute hypoxia-induced renal injury often progresses to chronic kidney disease (CKD), and the progressive loss of kidney function in CKD is linked to endothelial cell (EC) damage. The hypoxia-inducible transcription factors HIF-1 and HIF-2 are expressed in renal ECs following ischemic injury, but the specific contributions of these mediators to pathogenesis are not clear. In this issue of the Journal of Clinical Investigation, Volker Haase and colleagues at the Vanderbilt University School of Medicine used murine models of hypoxic kidney injury, to evaluate the contribution of endothelial HIF-1 and HIF-2 toward the development of ischemia-induced pathogenesis. Loss of HIF-2 alone markedly increased kidney inflammation and fibrosis following ischemic injury and was associated with increased expression of the neutrophil adhesion molecule VCAM1. Blocking VCAM1 in HIF-2-deficient mice reduced hypoxia-associated phenotypes. Furthermore, enhancing HIF-2 activation in WT mice prior to ischemia and reperfusion protected animals from kidney injury. Together, these data indicate that endothelial HIF-2 protects kidney from hypoxia-induced damage.

TITLE: Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury

AUTHOR CONTACT: Volker Hans Haase
Vanderbilt University, Nashville, TN, USA
Phone: 615 343-7254; Fax: 615 322-6854; E-mail:

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TITLE: Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density

AUTHOR CONTACT: Charles Farber
University of Virgina, Charlottesville, VA, USA
Phone: 434-243-8584; E-mail:

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TITLE: MicroRNA-7a regulates pancreatic β cell function

AUTHOR CONTACT: Markus Stoffel
Institute of Molecular Health Sciences, ETH Zurich, Zurich, UNK, CHE
Phone: +41 44 633 4560; E-mail:

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TITLE: MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection

AUTHOR CONTACT: Carole Guillonneau
INSERM UMR1064, Nantes, FRA
Phone: 33 02 40 08 75 96; E-mail:

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TITLE: ER stress regulates myeloid-derived suppressor cell fate through TRAIL-Rmediated apoptosis

AUTHOR CONTACT: Dmitry I. Gabrilovich
The Wistar Institute, Philadelphia, PA, USA
Phone: 215-495-6955; Fax: ; E-mail:

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TITLE: MicroRNA-486dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophyassociated symptoms

Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
Phone: 617.355.6729; Fax: 617.730.0253; E-mail:

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TITLE: Type I IFN signaling in CD8 DCs impairs Th1-dependent malaria immunity

AUTHOR CONTACT: Ashraful Haque
Queensland Institute of Medical Research, Brisbane, UNK, AUS
Phone: +61738453948; Fax: +61738453507; E-mail:

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Contact: Corinne Williams
Journal of Clinical Investigation

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