Calcium (Ca) ions play a central role in determining the waveshape of the action potential and the strength of contraction in cardiac muscle. The long term objectives of this research are 1) to define the cellular and molecular basis for the control of cytosolic Ca in normal and diseased cardiac muscle and 2) to characterize specific membrane proteins involved in Ca homeostasis and determine how they are regulated during normal growth and during the response to hemodynamic overload states which cause dysfunctional hypertrophy and lead to congestive heart failure (CHF). These issues are of particular importance in CHF because in this condition the electromechanical properties of the heart are abnormal. This study will define the cellular defects in Ca homeostasis which contribute to these abnormalities.
The specific aims of this research are: 1) To move fully characterize a recently developed animal model of pressure overload- induced LV hypertrophy and failure. 2. To define the changes in electromechanical properties and Ca homeostasis of myocytes isolated from failing feline LV. 3) To determine if changes in excitation-contraction coupling play a role in the weakened contractile state of failing myocytes. These studies will determine if changes in """"""""L type"""""""" Ca current and/or Ca- induced Ca release can explain the dysfunctional contractile of the sarcoplasmic reticulum produces the alterations in diastolic Ca and systolic Ca transients that are observed in failing myocytes. 5. To determine if the diminished beta-adrenergic responsiveness of the failing heart results from alterations in either B1- and/or B2-receptor density or effector coupling. Myocytes isolated from normal and failing (progressive LV pressure overload) feline ventricular muscle will be used. Ca currents will be measured using Indo-1. Pharmacological and molecular approaches will be used to study beta-adrenergic receptors. These experiments should provide new insight into the role of abnormal Ca homeostasis in CHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033921-08
Application #
3346306
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-06-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Borghetti, Giulia; von Lewinski, Dirk; Eaton, Deborah M et al. (2018) Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol 9:1514
Wang, Wei Eric; Li, Liangpeng; Xia, Xuewei et al. (2017) Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury. Circulation 136:834-848
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Sharp 3rd, Thomas E; Schena, Giana J; Hobby, Alexander R et al. (2017) Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction. Circ Res 121:1263-1278
Cho, Gun-Sik; Lee, Dong I; Tampakakis, Emmanouil et al. (2017) Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. Cell Rep 18:571-582
Troupes, Constantine D; Wallner, Markus; Borghetti, Giulia et al. (2017) Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction. Circ Res 121:125-136
Wallner, Markus; Eaton, Deborah M; Berretta, Remus M et al. (2017) A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function. Sci Rep 7:16587
Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott et al. (2016) Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circ Res 118:1143-50; discussion 1150
Wallner, Markus; Duran, Jason M; Mohsin, Sadia et al. (2016) Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration. Circ Res 119:865-79
Leipsic, Jonathon A (2015) President's Page. J Cardiovasc Comput Tomogr 9:604-5

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