In vivo left ventricular functional capacity is compromised in cMyBP-C null mice

Abstract

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein that binds tightly to myosin and has a potential role for modulating myocardial contraction. We tested the hypothesis that cMyBP-C 1) contributes to the enhanced in vivo contractile state following ␤-adrenergic stimulation and 2) is necessary for myocardial adaptation to chronic increases in afterload. In vivo pressure-volume relations demonstrated that left ventricular (LV) systolic and diastolic function were compromised under basal conditions in cMyBP-C Ϫ/Ϫ compared with WT mice. Moreover, whereas ␤-adrenergic treatment significantly improved ejection fraction, peak elastance, and the time to peak elastance in WT mice, these functional indexes remained unchanged in cMyBP-C Ϫ/Ϫ mice. Morphological and functional changes were measured through echocardiography in anesthetized mice following 5 wk of aortic banding. Adaptation to pressure overload was diminished in cMyBP-C Ϫ/Ϫ mice as characterized by a lack of an increase in posterior wall thickness, increased LV diameter, deterioration of fractional shortening, and prolonged isovolumic relaxation time. These results suggest that the absence of cMyBP-C significantly diminishes in vivo LV function and markedly attenuates the increase in LV contractility following ␤-adrenergic stimulation or adaptation to pressure overload. aortic banding; pressure-volume relations; dobutamine CARDIAC MYOSIN BINDING protein-C (cMyBP-C) is a thick filament accessory protein located within the C-zone of the Aband (3, 33) and is a significant determinant of structural integrity and muscle contractile regulation (12,26,38). The COOH terminus binds to the myosin rod (8) and to titin (6), thereby stabilizing the thick filament. The NH 2 terminus binds to the S2 segment of myosin near the lever arm and to actin and possesses phosphorylation sites that are thought to regulate the interaction of myosin and actin through PKA (7,11,24). The role of cMyBP-C is of particular interest in cardiac muscle because it is a physiological substrate for PKA and, thereby, is believed to play a role in the ␤-adrenergic effects on myocardial contraction (1,5,40).Numerous studies have investigated the effects of targeted cMyBP-C gene ablation (cMyBP-C Ϫ/Ϫ ) on cardiac structure and function. Mice lacking cMyBP-C display a profound hypertrophic response with reduced ejection, prolonged relaxation (12), an increased rate of ventricular stiffening during isovolumic contraction, and decreased peak elastance (E max ) (26). These studies suggest that cMyBP-C is important for normal systolic and diastolic function, possibly by modulating the rate of cross-bridge cycling and/or availability of cross bridges to actin (34,35); that is, cMyBP-C is normally repressive in this regard, but this effect is relieved following ablation of cMyBP-C.Less is known about the specific effects of ␤-adrenergic stimulation on cMyBP-C. ␤-Adrenergic stimulation of cardiac muscle results in the PKA-mediated phosphorylation of cardiac troponin I (TnI) and c...

Doppler Estimation of Reduced Coronary Flow Reserve in Mice with Pressure Overload Cardiac Hypertrophy

“…The reported increase in HW/BW is 16% at 7 days (Li et al, 2003), 38% at 21 days (Hamawaki et al, 1998;Tanaka et al, 1996), and as much as 56% at 35 days (Brickson et al, 2006). Our values for HW/BW of 8.3 mg/g in the present study correspond to an increase of 44% when compared to controls done previously by our group using similar methods (5.77 mg/g) (Li et al, 2003).…”

“…It is thought that decompensated heart failure ensues only after cardiac and coronary reserves are exhausted (Rushmer, 1976;Fallen et al, 1967;Vatner and Hittinger, 1993;Hittinger et al, 1989). Now that mice are being used as cardiovascular disease models (Niebauer et al, 1999;Rockman et al, 1993;Brickson et al, 2006;Barrick et al, 2007;Tanaka et al, 1996;Maslov et al, 2007), it is important to determine if the changes in myocardial perfusion and reserve in the face of increased loading conditions are similar in mice, humans, and larger mammals.…”

“…Transverse aortic banding induces pressure overload cardiac hypertrophy in mice and is used to stress normal, old, and genetically altered mice to study cardiac function and remodeling (Rockman et al, 1993;Li et al, 2003;Brickson et al, 2006;Barrick et al, 2007). Banded mice have significantly elevated HW/BW after 1-5 weeks, some show signs of heart failure, and many die within 3 to 5 weeks after banding (Barrick et al, 2007).…”

Control of In Vivo Contraction/Relaxation Kinetics by Myosin Binding Protein C

“…Genetically modified mice lacking cMyBP-C develop dilated cardiomyopathy with a reduced ejection fraction and end-systolic elastance. [25][26][27][28] Intriguingly, however, the peak rate of pressure rise (dP/ dt max ), a property that almost always decreases in failing hearts, is preserved in those lacking cMyBP-C. [25][26][27][28] One mechanism appears related to an unusual abbreviation of systole in such hearts, 26 which limits ejection. The impact of this behavior on other key features of heart contraction remains unexplored.…”

Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein

“…Control mice were housed under identical conditions without verapamil. The heart rate and blood pressure of control and verapamil-treated mice were assessed as described previously (3).…”