Mechanical strain is a powerful stimulus for shape and size remodeling of cardiac myocytes in normal and pathological situations. Indeed, the major change in shape that precedes heart failure in humans is progression to cellular elongation in dilated cardiomyopathy. The overall objective of this project is to test the hypothesis that longitudinal mechanical strain regulates cell lengthening by differential phosphorylation of focal adhesion kinase (FAK) at the costamere leading to differential actin capping by CapZ at the Z-disc and thin filament addition.
The Specific Aims are:
Aim #1 : To determine the mechanisms of anisotropic Rho family G protein phosphorylation leading to myocyte elongation. We define the subcellular events responsible for strain-induced PKCE signaling using the PKCE-over expressing (OE) mouse, and aligned 3D cultured neonatal rat ventricular myocytes (NRVM) subjected to sudden static strain as model systems.
Aim #2 : To test the hypothesis that PKC-dependent FAK serine phosphorylation is required for the costameric mechanosensory apparatus to detect longitudinal strain. We examine the PKC dependence of FAK serine phosphorylation in response to longitudinal vs. transverse strain in 3D NRVM cultures.
Aim #3 : To determine whether elongating myocytes have altered CapZ phosphorylation. We determine whether CapZ phosphorylations in normal mice differ from ventricular myocytes that are lengthening and whether there is differential CapZ phosphorylation in response to anisotropic mechanical inputs to NRVM aligned 3D culture.
Aim #4 : To test the hypothesis that CapZ phosphorylation and PIP2 binding alter actin capping and are required for length remodeling. We measure actin-capping dynamics of green fluorescent tagged-CapZ to determine the effect of anisotropic mechanical stimuli. We determine the mechanism of cell length remodeling by regulation of CapZ binding via phosphorylation, PIP2 and other CapZ partnering proteins. In these experiments, we use validated conditions of normal myocyte lengthening and challenge these processes with specific molecular interventions to determine the mechanisms of length remodeling.
Heart failure is a complex disorder affecting over 5 million Americans. It remains the leading discharge diagnosis of hospitalized patients over the age of 65, and has an overall 5-year mortality rate approaching 40%, even with optimal medical therapy. Clearly, investigations targeted at improving our understanding of the fundamental process of cardiac remodeling are necessary to reduce the incidence and prevalence of this syndrome, which would have significant impact on the health and longevity of the American public.
|Dvornikov, Alexey V; de Tombe, Pieter P; Xu, Xiaolei (2018) Phenotyping cardiomyopathy in adult zebrafish. Prog Biophys Mol Biol 138:116-125|
|Le, Long V; Mohindra, Priya; Fang, Qizhi et al. (2018) Injectable hyaluronic acid based microrods provide local micromechanical and biochemical cues to attenuate cardiac fibrosis after myocardial infarction. Biomaterials 169:11-21|
|Mkrtschjan, Michael A; Gaikwad, Snehal B; Kappenman, Kevin J et al. (2018) Lipid signaling affects primary fibroblast collective migration and anchorage in response to stiffness and microtopography. J Cell Physiol 233:3672-3683|
|Yan, Jiajie; Thomson, Justin K; Zhao, Weiwei et al. (2018) Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia. J Am Coll Cardiol 71:1459-1470|
|Bohlooli Ghashghaee, Nazanin; Li, King-Lun; Solaro, R John et al. (2018) Role of the C-terminus mobile domain of cardiac troponin I in the regulation of thin filament activation in skinned papillary muscle strips. Arch Biochem Biophys 648:27-35|
|Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K et al. (2018) Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ Res 122:821-835|
|Ait Mou, Younss; Lacampagne, Alain; Irving, Thomas et al. (2018) Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy. J Mol Cell Cardiol 114:345-353|
|Ferrantini, Cecilia; Coppini, Raffaele; Pioner, Josè Manuel et al. (2017) Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models. J Am Heart Assoc 6:|
|Alves, Marco L; Warren, Chad M; Simon, Jillian N et al. (2017) Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice. Cardiovasc Res 113:915-925|
|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|
Showing the most recent 10 out of 283 publications