Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling

Rajesh Katare, Andrea Caporali, Lorena Zentilin, Elisa Avolio, Graciela Sala-Newby, Atsuhiko Oikawa, Daniela Cesselli, Antonio Paolo Beltrami, Mauro Giacca, Costanza Emanueli, Paolo Madeddu

Research output: Contribution to journalArticle

Abstract

Rationale: Studies in transgenic mice showed the key role of (Pim-1) (proviral integration site for Moloney murine leukemia virus-1) in the control of cardiomyocyte function and viability. Objective: We investigated whether Pim-1 represents a novel mechanistic target for the cure of diabetic cardiomyopathy, a steadily increasing cause of nonischemic heart failure. Methods and Results: In streptozotocin-induced type 1 diabetic mice, Pim-1 protein levels declined during progression of cardiomyopathy, along with upregulation of Pim-1 inhibitors, protein phosphatase 2A, and microRNA-1. Moreover, diabetic hearts showed low levels of antiapoptotic B-cell lymphoma-2 (Bcl-2) protein and increased proapoptotic caspase-3 activity. Studies on adult rat cardiomyocytes and murine cardiac progenitor cells challenged with high glucose confirmed the in vivo expressional changes. In rescue studies, anti-microRNA-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocyte and cardiac progenitor cell survival under high glucose conditions. Similarly, transfection with Pim-1 plasmid prevented high glucose-induced cardiomyocyte and cardiac progenitor cell apoptosis. Finally, a single intravenous injection of human PIM-1 via cardiotropic serotype-9 adeno-associated virus (1×10 10 or 5×1010 plaque-forming units per animal) at 4 weeks after diabetes induction led to sustained cardiac overexpression of Pim-1 and improved diastolic function and prevented left ventricular dilation and failure. Histological examination showed reduced cardiomyocyte apoptosis and fibrosis in association with increased c-kit cells and cardiomyocyte proliferation, whereas molecular analysis confirmed activation of the prosurvival pathway and conservation of sarcoendoplasmic reticulum Ca 2+-ATPase and α-myosin heavy chain in Pim-1-treated hearts. Conclusions: Pim-1 downregulation contributes in the pathogenesis of diabetic cardiomyopathy. Systemic delivery of human PIM-1 via cardiotropic adeno-associated virus serotype-9 represents a novel and effective approach to treat diabetic cardiomyopathy.

Original languageEnglish
Pages (from-to)1238-1251
Number of pages14
JournalCirculation Research
Volume108
Issue number10
DOIs
Publication statusPublished - May 13 2011

Keywords

  • cardiac stem cells
  • diabetic cardiomyopathies
  • diastolic dysfunction
  • gene therapy
  • Pim-1 kinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling'. Together they form a unique fingerprint.

  • Cite this

    Katare, R., Caporali, A., Zentilin, L., Avolio, E., Sala-Newby, G., Oikawa, A., Cesselli, D., Beltrami, A. P., Giacca, M., Emanueli, C., & Madeddu, P. (2011). Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circulation Research, 108(10), 1238-1251. https://doi.org/10.1161/CIRCRESAHA.110.239111