The long-term objective of our research is to understand the mechanism and regulation of atrial natriuretic factor (ANF) biosynthesis, processing, and secretion. The proposal is focused on various treatments regulate ANF release. Our approach will involve the use of several cultured cell mode] systems and combination with biochemical and molecular biological techniques. Perhaps the greatest importance will be the use of our recently described serum-free long-term cultured heart cell system that mimic ANF processing and secretion as they occur in vivo.
Specific Aims : 1) To determine the cell type responsible for ANF processing, cardiocytes and cardiac mesenchymal cells (e.g. fibroblasts, endothelial cells) will cultured separately and their abilities to process endogenous (cardiocytes) or exogenous pro-ANF will be assessed. 2) The characteristics of the immunoreactive pro-thrombin associated with the heart and cultured cardiocytes will be studied using Western analysis, peptide mapping, radiosequencing, and message characterization. The possible involvement of the atrial thrombin-like material in pro-ANF processing will be assessed. 3) ANF will be expressed in several types of endocrine cells to determine whether the unusual thrombin-like co-/post-secretional cleavage at a single basic amino acid that occurs during pro-ANF maturation is a tissue- or hormone-specific phenomenon. 4) Adrenergic receptor activation, electrical pacing of contraction rate, and changes in cellular tension will be studied as models of acutely regulating ANF secretion, and it will be determined whether these treatments regulate ANF release at the level of the cardiocyte and what intracellular messengers are involved. The proposed studies will contribute new information to our knowledge of the factors that regulate plasma levels of ANF. Such information will help us understand the hemodynamic roles of ANF in both normal and pathological states, and will provide a foundation for the future rational design of ANF-related antihypertensives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025037-06
Application #
3410117
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1986-12-01
Project End
1994-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
San Diego State University
Department
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Glembotski, Christopher C (2014) Roles for ATF6 and the sarco/endoplasmic reticulum protein quality control system in the heart. J Mol Cell Cardiol 71:11-5
Meex, Steven J R; Weissglas-Volkov, Daphna; van der Kallen, Carla J H et al. (2009) The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels. Arterioscler Thromb Vasc Biol 29:1322-7
Glembotski, Christopher C (2008) The role of the unfolded protein response in the heart. J Mol Cell Cardiol 44:453-9
Glembotski, Christopher C (2007) Getting a G--RRP on regulated exocytosis in the heart. J Cell Biol 179:371-3
Thuerauf, Donna J; Marcinko, Marie; Belmont, Peter J et al. (2007) Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. J Biol Chem 282:22865-78
Martindale, Joshua J; Fernandez, Rayne; Thuerauf, Donna et al. (2006) Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res 98:1186-93
Kato, Takahiro; Muraski, John; Chen, Yan et al. (2005) Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt. J Clin Invest 115:2716-30
Martindale, Joshua J; Wall, Jason A; Martinez-Longoria, Diana M et al. (2005) Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem 280:669-76
Thuerauf, Donna J; Morrison, Lisa; Glembotski, Christopher C (2004) Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem 279:21078-84
Morrison, Lisa E; Whittaker, Ross J; Klepper, Robert E et al. (2004) Roles for alphaB-crystallin and HSPB2 in protecting the myocardium from ischemia-reperfusion-induced damage in a KO mouse model. Am J Physiol Heart Circ Physiol 286:H847-55

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