Congestive heart failure (CHF) is associated with an abnormality in cardiac cell function. The molecular mechanisms that underlie this depressed function in CHF are unknown. In previous work we have shown that myofilament function is depressed in CHF in terms of depressed maximum force generating capacity, calcium responsiveness, and cross-bridge cycle kinetics. Experimental mechanical/biochemical data suggest that dys-regulated myofilament contractile protein phosphorylation causes myofilament dysfunction in CHF, possibly via altered phosphorylation of myosin light chain (MLC), myosin binding protein C (MyoBPC), and Troponin-l (Tnl). However, the precise structure-function relationship has not been determined. In this proposal for continued support we will employ a well-established model of CHF in the guinea-pig secondary to pressure overload. The guinea-pig model allows study of control, compensatory hypertrophy, and CHF in a model that closely resembles the myofilament and EC-coupling parameters as found in the human. Biochemical proteomics analysis will be used to identify pathways and proteins that are targeted in CHF and the impact of identified post-translational modifications on contractile function will be determined using a variety of biophysical techniques ranging from intact electrically stimulated isolated muscle to single myofibrils (aim 1). Contractile protein post-translational modifications and signal pathways will be manipulated via adenoviral gene delivery, kinase/phosphatase treatment and recombinant protein contractile protein exchange in permeabilized isolated myocardium (aim 1). As we recently demonstrated, regional myofilament function is not uniform in the heart and this distribution is significantly altered in heart failure. Experiments proposed in specific aim 2 will determine the signal pathways and contractile protein posttranslational modifications that underlie these phenomena. Finally, experiments proposed in aim3 will determine the dynamic and temporal coupling between the driving Ca2+ transient and the mechanical dynamic contractile protein force production;these experiments will be performed in single cardiac myofibrils. Overall, our aim is to determine the mechanisms that underlie contractile protein dysfunction in CHF. Our research will aid in the development of new therapeutic strargies to combat OHF in patients.
Heart failure is a leading cause of mortality and mobidity. We have demonstrated that one defect causing heart failure is dysfunction of the contractile proteins in the heart. Our research is designed to determine what biochemical changes occur; which pathways are responsible; and how these changes can b e reversed; the ultimate goal is to develop novel therapies that target contractile protein dysfunction.
|Broughton, Kathleen M; Russell, Brenda (2015) Cardiomyocyte subdomain contractility arising from microenvironmental stiffness and topography. Biomech Model Mechanobiol 14:589-602|
|Carley, Andrew N; Taglieri, Domenico M; Bi, Jian et al. (2015) Metabolic efficiency promotes protection from pressure overload in hearts expressing slow skeletal troponin I. Circ Heart Fail 8:119-27|
|Simon, Jillian N; Chowdhury, Shamim A K; Warren, Chad M et al. (2014) Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation. Basic Res Cardiol 109:445|
|Kirk, Jonathan A; Holewinski, Ronald J; Kooij, Viola et al. (2014) Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3*. J Clin Invest 124:129-38|
|van der Velden, Jolanda; de Tombe, Pieter P (2014) Heart failure: a special issue. Pflugers Arch 466:1023|
|Alegre-Cebollada, Jorge; Kosuri, Pallav; Giganti, David et al. (2014) S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding. Cell 156:1235-46|
|Samarel, Allen M (2014) Focal adhesion signaling in heart failure. Pflugers Arch 466:1101-11|
|Bovo, Elisa; de Tombe, Pieter P; Zima, Aleksey V (2014) The role of dyadic organization in regulation of sarcoplasmic reticulum Ca(2+) handling during rest in rabbit ventricular myocytes. Biophys J 106:1902-9|
|Koshman, Yevgeniya E; Chu, Miensheng; Kim, Taehoon et al. (2014) Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy. J Mol Cell Cardiol 72:281-91|
|Wang, Rui; Wang, Yanwen; Lin, Wee K et al. (2014) Inhibition of angiotensin II-induced cardiac hypertrophy and associated ventricular arrhythmias by a p21 activated kinase 1 bioactive peptide. PLoS One 9:e101974|
Showing the most recent 10 out of 214 publications