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Circ Res. 2011 May 13;108(10):1238-51. doi: 10.1161/CIRCRESAHA.110.239111. Epub 2011 Apr 7.

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

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1
Department of Experimental Cardiovascular Medicine, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.

Erratum in

  • Circ Res. 2011 Oct 14;109(9):e52.

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 × 10(10) 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.

PMID:
21474815
DOI:
10.1161/CIRCRESAHA.110.239111
[Indexed for MEDLINE]

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