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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062426-15
Application #
8629552
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$386,169
Indirect Cost
$100,547
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zak, Taylor J; Koshman, Yevgenia E; Samarel, Allen M et al. (2017) Regulation of Focal Adhesion Kinase through a Direct Interaction with an Endogenous Inhibitor. Biochemistry 56:4722-4731
Ryba, David M; Li, Jieli; Cowan, Conrad L et al. (2017) Long-Term Biased ?-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy. Circulation 135:1056-1070
Ait-Mou, Younss; Zhang, Mengjie; Martin, Jody L et al. (2017) Impact of titin strain on the cardiac slow force response. Prog Biophys Mol Biol 130:281-287
Karam, Chehade N; Warren, Chad M; Henze, Marcus et al. (2017) Peroxisome proliferator-activated receptor-? expression induces alterations in cardiac myofilaments in a pressure-overload model of hypertrophy. Am J Physiol Heart Circ Physiol 312:H681-H690
Li, King-Lun; Ghashghaee, Nazanin Bohlooli; Solaro, R John et al. (2016) Sarcomere length dependent effects on the interaction between cTnC and cTnI in skinned papillary muscle strips. Arch Biochem Biophys 601:69-79
de Tombe, Pieter P; ter Keurs, Henk E D J (2016) Cardiac muscle mechanics: Sarcomere length matters. J Mol Cell Cardiol 91:148-50
Broughton, K M; Li, J; Sarmah, E et al. (2016) A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation. Am J Physiol Heart Circ Physiol 311:H107-17
Paudyal, Anju; Dewan, Sukriti; Ikie, Cindy et al. (2016) Nuclear accumulation of myocyte muscle LIM protein is regulated by heme oxygenase 1 and correlates with cardiac function in the transition to failure. J Physiol 594:3287-305
Siddiqui, Jalal K; Tikunova, Svetlana B; Walton, Shane D et al. (2016) Myofilament Calcium Sensitivity: Consequences of the Effective Concentration of Troponin I. Front Physiol 7:632
Abraham, Dennis M; Davis 3rd, Robert T; Warren, Chad M et al. (2016) ?-Arrestin mediates the Frank-Starling mechanism of cardiac contractility. Proc Natl Acad Sci U S A 113:14426-14431

Showing the most recent 10 out of 274 publications