Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010

Roberto Bolli; Atul R. Chugh; Domenico D'Amario; Marcus F. Stoddard; Sohail Ikram; Stephen G. Wagner; Garth M. Beache; Annarosa Leri; Toru Hosoda; John H. Loughran; Polina Goihberg; Claudia Fiorini; Naresh K. Solankhi; Ibrahim Fahsah; Arka Chatterjee; Julius B. Elmore; D. G. Rokosh; Mark S. Slaughter; Jan Kajstura; Piero Anversa

doi:10.1161/RES.0b013e3182014899

Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010

Roberto Bolli, Atul R. Chugh, Domenico D'Amario, Marcus F. Stoddard, Sohail Ikram, Stephen G. Wagner, Garth M. Beache, Annarosa Leri, Toru Hosoda, John H. Loughran, Polina Goihberg, Claudia Fiorini, Naresh K. Solankhi, Ibrahim Fahsah, Arka Chatterjee, Julius B. Elmore, D. G. Rokosh, Mark S. Slaughter, Jan Kajstura, Piero Anversa

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

2 Scopus citations

Abstract

Background: Studies in transgenic mice showed the key role of moloney murine leukemia virus 1 (Pim-1) in the control of cardiomyocyte function and viability. Objective: To investigate if Pim-1 is a therapeutic target for the cure of diabetic cardiomyopathy (DCM), a steadily increasing cause of non-ischemic heart failure. Methods and Results: Western blot analysis on hearts of streptozotocin-induced type-1 (T1D) mice showed a time-dependent reduction in Pim-1 (8-fold at 20 wks from T1D induction), a parallel decline in the Pim-1 activators STAT-3 (6-fold) and Akt (7-fold) and an increase of the Pim-1 direct inhibitor miR-1 (6-fold) (P 0.01 vs. age-matched non-diabetic (ND) mice for all comparisons). Moreover, diabetic hearts showed low levels of anti-apoptotic Bcl-2, high levels of pro-apoptotic Bad and increased caspase 3/7 activity (P<0.01 vs. ND for all comparisons). Studies on murine cardiomyocytes challenged with high glucose (HG) confirmed the in vivo expressional changes. In in vitro rescue studies, anti-miR-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocytes survival under HG. Similarly, transfection with Pim-1 plasmid prevented cardiomyocyte apoptosis. Finally, at 4 wks from T1D induction, mice were randomly assigned to receive an i.v. injection of human (h) Pim-1 via cardiotropic serotype-9 adeno-associated virus (1X1010 or 5X1010 pfu, doses decided on pilot titration studies) or empty vector. Expression of hPim-1 was confirmed by Western blot and immunohistochemistry in cardiomyocytes and to a less extent in skeletal muscles (Fig.1a), but not in other organs. Echocardiography showed that hPim-1 gene therapy attenuates diastolic dysfunction and prevents the development of left ventricle dilatation and failure in T1D mice (Fig.1b). Conclusion: Down-regulation of pro-survival Pim-1 contributes in the pathogenesis of DCM. Systemic delivery of hPim-1 via cardiotropic AAV9 represents a novel and effective approach to treat DCM.

Original language	English (US)
Pages (from-to)	e32-e40
Journal	Circulation research
Volume	107
Issue number	12
DOIs	https://doi.org/10.1161/RES.0b013e3182014899
State	Published - Dec 10 2010
Externally published	Yes

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine

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10.1161/RES.0b013e3182014899

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Bolli, R., Chugh, A. R., D'Amario, D., Stoddard, M. F., Ikram, S., Wagner, S. G., Beache, G. M., Leri, A., Hosoda, T., Loughran, J. H., Goihberg, P., Fiorini, C., Solankhi, N. K., Fahsah, I., Chatterjee, A., Elmore, J. B., Rokosh, D. G., Slaughter, M. S., Kajstura, J., & Anversa, P. (2010). Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010. Circulation research, 107(12), e32-e40. https://doi.org/10.1161/RES.0b013e3182014899

Bolli, R, Chugh, AR, D'Amario, D, Stoddard, MF, Ikram, S, Wagner, SG, Beache, GM, Leri, A, Hosoda, T, Loughran, JH, Goihberg, P, Fiorini, C, Solankhi, NK, Fahsah, I, Chatterjee, A, Elmore, JB, Rokosh, DG, Slaughter, MS, Kajstura, J & Anversa, P 2010, 'Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010', Circulation research, vol. 107, no. 12, pp. e32-e40. https://doi.org/10.1161/RES.0b013e3182014899

@article{c937d53bed044255978c2cc7b5a1a0d8,

title = "Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010",

abstract = "Background: Studies in transgenic mice showed the key role of moloney murine leukemia virus 1 (Pim-1) in the control of cardiomyocyte function and viability. Objective: To investigate if Pim-1 is a therapeutic target for the cure of diabetic cardiomyopathy (DCM), a steadily increasing cause of non-ischemic heart failure. Methods and Results: Western blot analysis on hearts of streptozotocin-induced type-1 (T1D) mice showed a time-dependent reduction in Pim-1 (8-fold at 20 wks from T1D induction), a parallel decline in the Pim-1 activators STAT-3 (6-fold) and Akt (7-fold) and an increase of the Pim-1 direct inhibitor miR-1 (6-fold) (P 0.01 vs. age-matched non-diabetic (ND) mice for all comparisons). Moreover, diabetic hearts showed low levels of anti-apoptotic Bcl-2, high levels of pro-apoptotic Bad and increased caspase 3/7 activity (P<0.01 vs. ND for all comparisons). Studies on murine cardiomyocytes challenged with high glucose (HG) confirmed the in vivo expressional changes. In in vitro rescue studies, anti-miR-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocytes survival under HG. Similarly, transfection with Pim-1 plasmid prevented cardiomyocyte apoptosis. Finally, at 4 wks from T1D induction, mice were randomly assigned to receive an i.v. injection of human (h) Pim-1 via cardiotropic serotype-9 adeno-associated virus (1X1010 or 5X1010 pfu, doses decided on pilot titration studies) or empty vector. Expression of hPim-1 was confirmed by Western blot and immunohistochemistry in cardiomyocytes and to a less extent in skeletal muscles (Fig.1a), but not in other organs. Echocardiography showed that hPim-1 gene therapy attenuates diastolic dysfunction and prevents the development of left ventricle dilatation and failure in T1D mice (Fig.1b). Conclusion: Down-regulation of pro-survival Pim-1 contributes in the pathogenesis of DCM. Systemic delivery of hPim-1 via cardiotropic AAV9 represents a novel and effective approach to treat DCM.",

author = "Roberto Bolli and Chugh, {Atul R.} and Domenico D'Amario and Stoddard, {Marcus F.} and Sohail Ikram and Wagner, {Stephen G.} and Beache, {Garth M.} and Annarosa Leri and Toru Hosoda and Loughran, {John H.} and Polina Goihberg and Claudia Fiorini and Solankhi, {Naresh K.} and Ibrahim Fahsah and Arka Chatterjee and Elmore, {Julius B.} and Rokosh, {D. G.} and Slaughter, {Mark S.} and Jan Kajstura and Piero Anversa",

year = "2010",

month = dec,

day = "10",

doi = "10.1161/RES.0b013e3182014899",

language = "English (US)",

volume = "107",

pages = "e32--e40",

journal = "Circulation research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

TY - JOUR

T1 - Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010

AU - Bolli, Roberto

AU - Chugh, Atul R.

AU - D'Amario, Domenico

AU - Stoddard, Marcus F.

AU - Ikram, Sohail

AU - Wagner, Stephen G.

AU - Beache, Garth M.

AU - Leri, Annarosa

AU - Hosoda, Toru

AU - Loughran, John H.

AU - Goihberg, Polina

AU - Fiorini, Claudia

AU - Solankhi, Naresh K.

AU - Fahsah, Ibrahim

AU - Chatterjee, Arka

AU - Elmore, Julius B.

AU - Rokosh, D. G.

AU - Slaughter, Mark S.

AU - Kajstura, Jan

AU - Anversa, Piero

PY - 2010/12/10

Y1 - 2010/12/10

N2 - Background: Studies in transgenic mice showed the key role of moloney murine leukemia virus 1 (Pim-1) in the control of cardiomyocyte function and viability. Objective: To investigate if Pim-1 is a therapeutic target for the cure of diabetic cardiomyopathy (DCM), a steadily increasing cause of non-ischemic heart failure. Methods and Results: Western blot analysis on hearts of streptozotocin-induced type-1 (T1D) mice showed a time-dependent reduction in Pim-1 (8-fold at 20 wks from T1D induction), a parallel decline in the Pim-1 activators STAT-3 (6-fold) and Akt (7-fold) and an increase of the Pim-1 direct inhibitor miR-1 (6-fold) (P 0.01 vs. age-matched non-diabetic (ND) mice for all comparisons). Moreover, diabetic hearts showed low levels of anti-apoptotic Bcl-2, high levels of pro-apoptotic Bad and increased caspase 3/7 activity (P<0.01 vs. ND for all comparisons). Studies on murine cardiomyocytes challenged with high glucose (HG) confirmed the in vivo expressional changes. In in vitro rescue studies, anti-miR-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocytes survival under HG. Similarly, transfection with Pim-1 plasmid prevented cardiomyocyte apoptosis. Finally, at 4 wks from T1D induction, mice were randomly assigned to receive an i.v. injection of human (h) Pim-1 via cardiotropic serotype-9 adeno-associated virus (1X1010 or 5X1010 pfu, doses decided on pilot titration studies) or empty vector. Expression of hPim-1 was confirmed by Western blot and immunohistochemistry in cardiomyocytes and to a less extent in skeletal muscles (Fig.1a), but not in other organs. Echocardiography showed that hPim-1 gene therapy attenuates diastolic dysfunction and prevents the development of left ventricle dilatation and failure in T1D mice (Fig.1b). Conclusion: Down-regulation of pro-survival Pim-1 contributes in the pathogenesis of DCM. Systemic delivery of hPim-1 via cardiotropic AAV9 represents a novel and effective approach to treat DCM.

AB - Background: Studies in transgenic mice showed the key role of moloney murine leukemia virus 1 (Pim-1) in the control of cardiomyocyte function and viability. Objective: To investigate if Pim-1 is a therapeutic target for the cure of diabetic cardiomyopathy (DCM), a steadily increasing cause of non-ischemic heart failure. Methods and Results: Western blot analysis on hearts of streptozotocin-induced type-1 (T1D) mice showed a time-dependent reduction in Pim-1 (8-fold at 20 wks from T1D induction), a parallel decline in the Pim-1 activators STAT-3 (6-fold) and Akt (7-fold) and an increase of the Pim-1 direct inhibitor miR-1 (6-fold) (P 0.01 vs. age-matched non-diabetic (ND) mice for all comparisons). Moreover, diabetic hearts showed low levels of anti-apoptotic Bcl-2, high levels of pro-apoptotic Bad and increased caspase 3/7 activity (P<0.01 vs. ND for all comparisons). Studies on murine cardiomyocytes challenged with high glucose (HG) confirmed the in vivo expressional changes. In in vitro rescue studies, anti-miR-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocytes survival under HG. Similarly, transfection with Pim-1 plasmid prevented cardiomyocyte apoptosis. Finally, at 4 wks from T1D induction, mice were randomly assigned to receive an i.v. injection of human (h) Pim-1 via cardiotropic serotype-9 adeno-associated virus (1X1010 or 5X1010 pfu, doses decided on pilot titration studies) or empty vector. Expression of hPim-1 was confirmed by Western blot and immunohistochemistry in cardiomyocytes and to a less extent in skeletal muscles (Fig.1a), but not in other organs. Echocardiography showed that hPim-1 gene therapy attenuates diastolic dysfunction and prevents the development of left ventricle dilatation and failure in T1D mice (Fig.1b). Conclusion: Down-regulation of pro-survival Pim-1 contributes in the pathogenesis of DCM. Systemic delivery of hPim-1 via cardiotropic AAV9 represents a novel and effective approach to treat DCM.

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Late-breaking basic science abstracts from the American Heart Association's Scientific Sessions 2010

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