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

doi:10.1161/CIRCRESAHA.110.239111

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^*

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

110 Citations (Scopus)

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 language	English
Pages (from-to)	1238-1251
Number of pages	14
Journal	Circulation Research
Volume	108
Issue number	10
DOIs	https://doi.org/10.1161/CIRCRESAHA.110.239111
Publication status	Published - 13 May 2011

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1161/CIRCRESAHA.110.239111

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

@article{4ce8b51181874c0299ec24f5830dcde5,

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

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.",

keywords = "cardiac stem cells, diabetic cardiomyopathies, diastolic dysfunction, gene therapy, Pim-1 kinase",

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

year = "2011",

month = may,

day = "13",

doi = "10.1161/CIRCRESAHA.110.239111",

language = "English",

volume = "108",

pages = "1238--1251",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

number = "10",

}

Katare, R, Caporali, A, Zentilin, L, Avolio, E, Sala-Newby, G, Oikawa, A, Cesselli, D, Beltrami, AP, 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, vol. 108, no. 10, pp. 1238-1251. https://doi.org/10.1161/CIRCRESAHA.110.239111

TY - JOUR

T1 - Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling

AU - Katare, Rajesh

AU - Caporali, Andrea

AU - Zentilin, Lorena

AU - Avolio, Elisa

AU - Sala-Newby, Graciela

AU - Oikawa, Atsuhiko

AU - Cesselli, Daniela

AU - Beltrami, Antonio Paolo

AU - Giacca, Mauro

AU - Emanueli, Costanza

AU - Madeddu, Paolo

PY - 2011/5/13

Y1 - 2011/5/13

N2 - 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.

AB - 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.

KW - cardiac stem cells

KW - diabetic cardiomyopathies

KW - diastolic dysfunction

KW - gene therapy

KW - Pim-1 kinase

UR - http://www.scopus.com/inward/record.url?scp=79957497037&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.110.239111

DO - 10.1161/CIRCRESAHA.110.239111

M3 - Article

C2 - 21474815

AN - SCOPUS:79957497037

SN - 0009-7330

VL - 108

SP - 1238

EP - 1251

JO - Circulation Research

JF - Circulation Research

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this