Cardiac myosin-binding protein-C is a critical mediator of diastolic function

Tong, Carl W.; Nair, Nandini; Doersch, Karen; Liu, Yang; Rosas, Paola C

doi:10.1007/s00424-014-1442-1

Cited by 37 publications

(31 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The rat develops HF in association with hyperglycemia and insulin resistance, and, therefore, while it may represent a good model for HFpEF with metabolic alterations, it is unlikely to be representative of all patients with HFpEF. Genetic modifications of titin and cardiac myosin binding protein C have also been proposed as models of HFpEF (12,25). These genetic models allow for the intrinsic changes to develop progressively as the mouse grows and ages, but do not reflect the clinical HFpEF syndrome.…”

Section: Discussionmentioning

confidence: 99%

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

Regan

Mauro

Carbone

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

A, Toldo S. A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II. Am J Physiol Heart Circ Physiol 309: H771-H778, 2015. First published July 17, 2015; doi:10.1152/ajpheart.00282.2015.-Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ϳ50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (AT II) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the AT II (0.2 mg·kg Ϫ1 ·day Ϫ1 ) or volume-matched vehicle (N ϭ 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. AT II infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose AT II recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.heart failure with preserved ejection fraction; diastolic dysfunction; animal model; angiotensin II; end-diastolic pressure; isovolumetric relaxation time NEW & NOTEWORTHY Chronic infusion of low-dose angiotensin II in the mouse induces diastolic dysfunction and HFpEF in the absence of pressure overload, LV systolic dysfunction, LV dilatation or hypertrophy, and metabolic abnormalities. This model may be considered a novel tool for mechanistic preclinical studies in HFpEF with translational potential.HEART FAILURE (HF) WITH PRESERVED ejection fraction (HFpEF) is a clinical syndrome of symptoms of HF, such as breathlessness and exercise intolerance, associated with impaired left ventricular (LV) diastolic function in the presence of a normal LV ejection fraction (LVEF Ͼ 50%) (2). HFpEF carries significant morbidity and mortality burdens, and the prevalence of the disease has increased over the past 30 yr (2, 17). To date, the mechanisms underlying diastolic dysfunction and the progression of HFpEF are poorly understood. The path...

show abstract

Section: Discussionmentioning

confidence: 99%

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

Regan

Mauro

Carbone

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…CARDIAC MYOSIN-BINDING PROTEIN-C. Cardiac myosin-binding protein-C (cMyBP-C) is a component of the thick filament in cardiomyocytes that modulates the cross-bridge attachment/ detachment cycling process (236). Experimental studies have suggested a potential role for cMyBP-C in diastolic function.…”

Section: Altered Signaling Pathways In Hfpef As Potential Targets Formentioning

confidence: 99%

Myocardial reverse remodeling: how far can we rewind?

Gonçalves-Rodrigues

Leite‐Moreira

Falcão-Pires

2016

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions.

show abstract

“…Our structural measurements suggest that eight residues on the α-helix of the triple-helix bundle that are buried when the MyBP-C motif is unphosphorylated become exposed, and overall motif dynamics become more stable, upon phosphorylation. Because cMyBP-C is likely to be highly phosphorylated under resting physiological conditions in healthy humans and studied mouse models of human heart disease, this uncovered helix may be an important binding region critical to normal cardiac function (26,28,32,33) and would certainly be the dominant cMyBP-C site during β-adrenergic stimulation with high phosphorylation levels, as occurs with the fight-or-flight acute stress response. Furthermore, because cMyBP-C phosphorylation decreases in patients with heart failure and hypertrophic cardiomyopathy (30,32,34), the loss of this exposed binding site could have markedly detrimental effects on the contractility response in failing hearts.…”

Section: Allosteric and Propagating Effects Of Cmybp-c Phosphorylatiomentioning

confidence: 99%

Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics

Colson

Thompson

Espinoza-Fonseca

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have used the site-directed spectroscopies of time-resolved fluorescence resonance energy transfer (TR-FRET) and double electronelectron resonance (DEER), combined with complementary molecular dynamics (MD) simulations, to resolve the structure and dynamics of cardiac myosin-binding protein C (cMyBP-C), focusing on the N-terminal region. The results have implications for the role of this protein in myocardial contraction, with particular relevance to β-adrenergic signaling, heart failure, and hypertrophic cardiomyopathy. N-terminal cMyBP-C domains C0-C2 (C0C2) contain binding regions for potential interactions with both thick and thin filaments. Phosphorylation by PKA in the MyBP-C motif regulates these binding interactions. Our spectroscopic assays detect distances between pairs of site-directed probes on cMyBP-C. We engineered intramolecular pairs of labeling sites within cMyBP-C to measure, with high resolution, the distance and disorder in the protein's flexible regions using TR-FRET and DEER. Phosphorylation reduced the level of molecular disorder and the distribution of C0C2 intramolecular distances became more compact, with probes flanking either the motif between C1 and C2 or the Pro/Ala-rich linker (PAL) between C0 and C1. Further insight was obtained from microsecond MD simulations, which revealed a large structural change in the disordered motif region in which phosphorylation unmasks the surface of a series of residues on a stable α-helix within the motif with high potential as a protein-protein interaction site. These experimental and computational findings elucidate structural transitions in the flexible and dynamic portions of cMyBP-C, providing previously unidentified molecular insight into the modulatory role of this protein in cardiac muscle contractility. muscle | protein kinase A | fluorescence resonance energy transfer | DEER | molecular dynamics simulation

show abstract

Cardiac myosin-binding protein-C is a critical mediator of diastolic function

Cited by 37 publications

References 46 publications

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

Myocardial reverse remodeling: how far can we rewind?

Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics

Contact Info

Product

Resources

About