Myocardial angiogenesis has been considered a therapeutic target for improving cardiac function by increasing perfusion, but clinical trials to deliver VEGF-A or FGF have not been successful and resulted in aberrant and leaky vessels. Considering that formation of vessels normally requires the concerted actions of multiple factors, we searched for mechanisms of coordinate transcriptional control of angiogenic factor genes. We present data that the transcription factor RBPJ regulates nearly all angiogenic genes examined in vivo. Cardiomyocyte-specific deletion of RBPJ [J Recombination signal sequence Binding Protein, aka CSL-1 and Suppressor of Hairless, Su(H)] in the adult mouse heart reveals that RBPJ represses angiogenic factor genes in the normal heart. Ischemic injury releases RBPJ-repression to stimulate an increase in microvessel density in the ventricular wall. Remarkably, genetic attenuation of RBPJ in cardiomyocytes preserves heart function and survival post-MI, possibly reflecting increased vessel density and/or direct protective effects of genes induced by the loss of RBPJ. The goal of this project is to define the mechanism(s) by which RBPJ promotes angiogenesis and myocardial protection after MI, and evaluate whether modulating RBPJ and/or its interacting proteins would therapeutically enhance these processes after ischemic or other injury.
Aims 1 and 2 evaluate the regulation of angiogenesis by defining the transcriptional basis for the coordinated control of angiogenic factor genes in normal and ischemic hearts (Aim 1) and verifying the functionality of the new vessels (Aim 2).
Aims 3 and 4 expand the project beyond angiogenesis to follow up additional preliminary data suggesting that inhibition RBPJ stimulates protective signal transduction pathways and changes in energy substrate utilization that might contribute to myocardial cell survival post-MI. In summary, this project will study a new paradigm for the control of myocardial angiogenesis and evaluate RBPJ and its interacting partners as candidate therapeutic targets for the treatment of ischemic heart disease.

Public Health Relevance

There is a large unmet need for discovery of novel targets for new pharmacological therapies for heart failure. The proposed experiments will use mouse transgenics to evaluate RBPJ and Notch as critical sensors of ischemic injury and potential therapeutic targets for treatment of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108176-02
Application #
8392245
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2011-12-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$464,098
Indirect Cost
$226,099
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Wei, Ke; Serpooshan, Vahid; Hurtado, Cecilia et al. (2015) Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature 525:479-85
Wei, Ke; Díaz-Trelles, Ramon; Liu, Qiaozhen et al. (2015) Developmental origin of age-related coronary artery disease. Cardiovasc Res 107:287-94
Okolotowicz, Karl J; Bushway, Paul; Lanier, Marion et al. (2015) 1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells. Bioorg Med Chem 23:5282-92
Cabral-Teixeira, Joaquim; Martinez-Fernandez, Almudena; Cai, Wenqing et al. (2015) Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells. Stem Cell Res 15:88-95
Spiering, Sean; Davidovics, Herman; Bushway, Paul J et al. (2015) High content screening for modulators of cardiac differentiation in human pluripotent stem cells. Methods Mol Biol 1263:43-61
Saccone, Valentina; Consalvi, Silvia; Giordani, Lorenzo et al. (2014) HDAC-regulated myomiRs control BAF60 variant exchange and direct the functional phenotype of fibro-adipogenic progenitors in dystrophic muscles. Genes Dev 28:841-57
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Willems, Erik; Mercola, Mark (2014) Reprogramming the cardiac field. Circ Res 114:409-11
Cai, Wenqing; Albini, Sonia; Wei, Ke et al. (2013) Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment. Genes Dev 27:2332-44

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