The Notch pathway, as well as potential regulators or effectors HIFa/Notch signaling, have emerged as particulariy relevant for establishing and maintaining heart funcfion under hypoxic stress conditions. We generated/collected mutafions of HIFa and Notch signaling in mulfiple cardiac compartments. We have gathered data suggesfing that genefic ablation of Notch pathway acfivity in the mouse myocardium does not lead to cardiac remodeling in response to hypoxic condifions caused by myocardial infarcfion, but rather has a protective effect on cardiomyocytes after the infarct. Moreover, in the Drosophila heart model, an acute response to hypoxia (slowing of the heart rate) does not occur when Notch signaling is acfivated in the heart, and chronic hypoxia leads to a non-contracfile, infarct-like condition of the heart. In contrast, HIF/Notch mutafions in the mouse epicardium are deleterious to heart funcfion, in that the response to transaortic constricfion is aggravated and cardiac hypertrophy is increased. Thus, the epicardium plays also a crifical role in the cardiac response to hypoxia. Thus, modulafion of HIF as well as Notch signaling in various cardiac compartments is crifical for the heart to respond and tolerate hypoxic conditions. We hypothesize that the interaction between HIF and Notch pathways are key to the regulafion of the response to hypoxia, that HIF/Notch signaling elicits unique responses in the myocardium versus the epicardium, and that the HIF/Notch-dependent mechanisms protect cardiac function. In this proposal, we will study the respective contribution and interacfions of HIF and Notch signaling to hypoxia tolerance and susceptibility in the heart. Based on the evolufionary conservafion of the hypoxia response, mechanisms of cardiac hypoxia responses identified in the fly heart, involving HIF and Notch signaling, promise to be of relevance to the mammalian heart. Insights gained here are likely to lead to new avenues for finding treatments for hypoxia-induced cardiac injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Walls, Stanley M; Cammarato, Anthony; Chatfield, Dale A et al. (2018) Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. Cell Rep 22:2702-2715
Zanon, Alessandra; Kalvakuri, Sreehari; Rakovic, Aleksandar et al. (2017) SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet 26:2412-2425
Diop, Soda Balla; Birse, Ryan T; Bodmer, Rolf (2017) High Fat Diet Feeding and High Throughput Triacylglyceride Assay in Drosophila Melanogaster. J Vis Exp :
Zarndt, Rachel; Walls, Stanley M; Ocorr, Karen et al. (2017) Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila. Circ Cardiovasc Genet 10:
Pamenter, Mathhew E; Powell, Frank L (2016) Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis. Compr Physiol 6:1345-85
Gan, Zhuohui; Fu, Zhenxing; Stowe, Jennifer C et al. (2016) A Protocol to Collect Specific Mouse Skeletal Muscles for Metabolomics Studies. Methods Mol Biol 1375:169-79
Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul et al. (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088
Hartley, Paul S; Motamedchaboki, Khatereh; Bodmer, Rolf et al. (2016) SPARC-Dependent Cardiomyopathy in Drosophila. Circ Cardiovasc Genet 9:119-29
Azad, Priti; Zhao, Huiwen W; Cabrales, Pedro J et al. (2016) Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease. J Exp Med 213:2729-2744
Dewan, Sukriti; McCabe, Kimberly J; Regnier, Michael et al. (2016) Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study. J Phys Chem B 120:8264-75

Showing the most recent 10 out of 82 publications