Abstract

In hearts subjected to chronic overload, compensatory growth of the myocardium commonly transitions into decompensated congestive heart failure over time. Recently, myocyte dropout by apoptotic cell death has been implicated in the decreased contractile function seen in the decompensated heart. We have previously determined that moderate activation of signaling pathways downstream of G?q cause hypertrophy in cardiac myocytes whereas high-level activation of these pathways results in apoptosis. We hypothesize that hyperactivation of G?q-mediated signaling in the overloaded heart could result in apoptotic myocyte dropout and contribute to the decreased contractility seen in the decompensated heart. We propose to confirm our in vitro findings which suggest apoptosis as the mechanism for G?q-induced myocyte death by assessing the effects of high-level G?q activation on the subcellular structures of individual myocytes. Early markers of decreased contractile function and apoptotic cell death will be evaluated using electron microscopy including; disruption of myofilament organization, appearance of cytoplasmic vaculoes, and changes in nuclear and mitochondrial membrane structure.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR004050-11S1
Application #
6220668
Study Section
Project Start
1999-05-15
Project End
2000-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Funakoshi, Shunsuke; Miki, Kenji; Takaki, Tadashi et al. (2016) Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. Sci Rep 6:19111
Rubio-Marrero, Eva N; Vincelli, Gabriele; Jeffries, Cy M et al. (2016) Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1. J Biol Chem 291:5788-802
Yin, Xinghua; Kidd, Grahame J; Ohno, Nobuhiko et al. (2016) Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling. J Cell Biol 215:531-542
Zhao, Claire Y; Greenstein, Joseph L; Winslow, Raimond L (2016) Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. J Mol Cell Cardiol 91:215-27
Sanders, Matthew A; Madoux, Franck; Mladenovic, Ljiljana et al. (2015) Endogenous and Synthetic ABHD5 Ligands Regulate ABHD5-Perilipin Interactions and Lipolysis in Fat and Muscle. Cell Metab 22:851-60
Takeshima, Hiroshi; Hoshijima, Masahiko; Song, Long-Sheng (2015) Ca²? microdomains organized by junctophilins. Cell Calcium 58:349-56
Mills, Elizabeth A; Davis, Chung-ha O; Bushong, Eric A et al. (2015) Astrocytes phagocytose focal dystrophies from shortening myelin segments in the optic nerve of Xenopus laevis at metamorphosis. Proc Natl Acad Sci U S A 112:10509-14
Kim, K-Y; Perkins, G A; Shim, M S et al. (2015) DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma. Cell Death Dis 6:e1839
Khakh, Baljit S; Sofroniew, Michael V (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942-52
Ju, Won-Kyu; Kim, Keun-Young; Noh, You Hyun et al. (2015) Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes. Glia 63:736-53

Showing the most recent 10 out of 384 publications