Myocardial infarction is a major health concern in the US. Patients that have suffered an Ml (heart attack) are usuually released from the hospital with a stable hemodynamic profile but with a dead portion of their heart (the ischemic zone). Over the next months/years there are major structural and functional remodeling of the post Ml heart that ultimately produce a dilated heart with poor contractile performance. In most instances, patients eventually develop dilated cardiomyopathy symptoms that culminate in congestive heart failure. Novel therapies that reduce post Ml structural and functional remodeling would improve patient health. Recent studies in many laboratories suggest that abnormilites in calcium (Ca) regulation within different cellular microdomains cause abnormalities in myocyte structure and function. In particular, there is evidence that the Ca signaling that induces pathological remodeling and contractile disturbances occurs within separate "signaling" and "excitation-contraction coupling" microdomains that both contain a poorly understood class of canonical transient receptor potential (TRPC) channels. Activation of TRPC channels has been linked to pathological hypertrophy and poor myocyte contractility. This project seeks to reduce excess TRPC channel activity to reduce cardiac structural and functional defects after Ml.
The Specific Aims are:1) To determine how TRPC channels interact with LTCCs and other Ca regulatory proteins within separate signaling and EC coupling microdomains to cause pathological hypertrophy and depressed contractility in cardiac disease.2) To determine if inhibition of TRPC activity after Ml (AAV-dnTRPC4 in pigs and in transgenic mice with dnTRPC4 expression) blunts post Ml ventricular remodeling, reduces pathological hypertrophy and enhances myocyte contractility to improve cardiac pump function. The research in this project will also explore how signaling pathways to be interrogated in the two other PPG projects alter TRPC channel function to influence pathological responses to stress. The project should define new knowledge regarding Ca signaling leading to cardiac dysfunction and approaches to abolish these processes to improve health of Ml patients.
Myocardial infarction (Ml) resulting from ischemic heart disease is a major health problem in the US and current Ml therapies are do not prevent the development of poor cardiac function. Our study explores the idea that blocking calcium entry via transient receptor potential channels will reduce structural and functional defects that develop in the heart after Ml.
|Wasilewski, Melissa A; Myers, Valerie D; Recchia, Fabio A et al. (2016) Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell Signal 28:224-33|
|Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang et al. (2016) BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. J Mol Cell Cardiol 92:10-20|
|Waldschmidt, Helen V; Homan, Kristoff T; Cruz-RodrÃguez, Osvaldo et al. (2016) Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem 59:3793-807|
|Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) Î²-arrestin-biased signaling through the Î²2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16|
|Grisanti, Laurel A; Gumpert, Anna M; Traynham, Christopher J et al. (2016) Leukocyte-Expressed Î²2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury. Circulation 134:153-67|
|Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito et al. (2016) Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nat Commun 7:10877|
|Zhou, Jibin; Ahmad, Firdos; Parikh, Shan et al. (2016) Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circ Res 118:1208-22|
|Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S et al. (2016) Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy. J Biol Chem 291:21913-21924|
|Traynham, Christopher J; Hullmann, Jonathan; Koch, Walter J (2016) "Canonical and non-canonical actions of GRK5 in the heart". J Mol Cell Cardiol 92:196-202|
|Khan, Mohsin; Koch, Walter J (2016) c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality. Circ Res 118:783-5|
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