Alpha1-adrenergic stimulation has two chronic, developmental or trophic effects in cultured neonatal rat heart muscle cells: stimulation of hypertrophy and induction of beating activity. The effect on beating requires concomitant Beta1-adrenergic stimulation. Hypertrophy and beating can be experimentally dissociated, suggesting dual Alpha1-mediated pathways, and these may be regulated by different products of inositol phospholipid hydrolysis. Hypertrophied cells produced by some growth factors do not beat and/or have no increase in contractile proteins; they can be considered to be pathologically hypertrophied cells. These findings and other preliminary data provide the basis for the four aims of this continuing work, related to relevance, mechanisms, other growth factors, and the variability of the hypertrophic response. First, the general relevance of Alpha1-mediated trophic effects will be tested by studies on heart muscle cell cultures from the human fetus and from other small mammals, fetal or neonatal and adult. Second, the mechanisms of Alpha1 tropic effects will be explored by studies of phosphoinositide turnover, Alpha1-receptor translocation and nuclear effects, and a myocyte renin-angiotensin system. The mechanisms underlying the beating response will be clarified (cell electrophysiology, contractile strength and velocity, high energy phosphates, cyclic nucleotides), and the Alpha1 and Beta1 contributions will be defined. Third, confirmatory evidence for autocrine myocyte growth factors will be sought by studies of the growth-promoting activity of heart extracts and conditioned medium. Static stretch as a growth factor will be tested. Fourth, the variability of the hypertrophic response to different growth factors will be described in terms of contractile protein content and turnover, myosin and creatine kinase isoforms, contractile activity, nerve growth factor mRNA expression, collagen synthesis, and DNA synthesis and mitosis. The long-range goal is to understand how normal and abnormal myocardial hypertrophy are controlled. The basic hypothesis is that myocardial cell growth and function are chronically regulated by signal-receptor mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031113-08
Application #
3342138
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1983-07-01
Project End
1993-04-30
Budget Start
1990-07-01
Budget End
1993-04-30
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
López, Javier E; Sharma, Janhavi; Avila, Jorge et al. (2017) Novel large-particle FACS purification of adult ventricular myocytes reveals accumulation of myosin and actin disproportionate to cell size and proteome in normal post-weaning development. J Mol Cell Cardiol 111:114-122
Simpson, Paul C; Myagmar, Bat-Erdene; Swigart, Philip M et al. (2017) Response by Simpson et al to Letter Regarding Article, ""Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent"". Circ Res 120:e56-e57
Beak, JuYoun; Huang, Wei; Parker, Joel S et al. (2017) An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity. JACC Basic Transl Sci 2:39-53
Myagmar, Bat-Erdene; Flynn, James M; Cowley, Patrick M et al. (2017) Adrenergic Receptors in Individual Ventricular Myocytes: The Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent. Circ Res 120:1103-1115
López, Javier E; Jaradeh, Katrin; Silva, Emmanuel et al. (2017) A method to increase reproducibility in adult ventricular myocyte sizing and flow cytometry: Avoiding cell size bias in single cell preparations. PLoS One 12:e0186792
Willis, Monte S; Ilaiwy, Amro; Montgomery, Megan D et al. (2016) The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo. Metabolomics 12:
Thomas, R Croft; Singh, Abhishek; Cowley, Patrick et al. (2016) A Myocardial Slice Culture Model Reveals Alpha-1A-Adrenergic Receptor Signaling in the Human Heart. JACC Basic Transl Sci 1:155-167
Simpson, Paul C (2015) A New Pathway for Sympathetic Cardioprotection in Heart Failure. Circ Res 117:592-5
Cowley, Patrick M; Wang, Guanying; Chang, Audrey N et al. (2015) The ?1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am J Physiol Heart Circ Physiol 309:H888-96
Shimkunas, Rafael; Makwana, Om; Spaulding, Kimberly et al. (2014) Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone. Am J Physiol Heart Circ Physiol 307:H1150-8

Showing the most recent 10 out of 60 publications