| المؤلفون: |
Ma W; BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL, USA., Del Rio CL; Cardiovascular Drug Discovery, Bristol Myers Squibb, Brisbane, CA 94005., Qi L; Department of Biology, Illinois Institute of Technology, Chicago, IL, USA., Prodanovic M; Institute for Information Technologies, University of Kragujevac, Kragujevac, Serbia.; FilamenTech, Inc., Newtown, MA 02458, USA., Mijailovich S; FilamenTech, Inc., Newtown, MA 02458, USA., Zambataro C; Cardiovascular Drug Discovery, Bristol Myers Squibb, Brisbane, CA 94005., Gong H; Department of Biology, Illinois Institute of Technology, Chicago, IL, USA., Shimkunas R; Cardiovascular Drug Discovery, Bristol Myers Squibb, Brisbane, CA 94005., Gollapudi S; Cardiovascular Drug Discovery, Bristol Myers Squibb, Brisbane, CA 94005., Nag S; Cardiovascular Drug Discovery, Bristol Myers Squibb, Brisbane, CA 94005., Irving TC; BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL, USA. |
| مستخلص: |
Mavacamten is a novel, FDA-approved, small molecule therapeutic designed to regulate cardiac function by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin towards ordered off states close to the thick filament backbone. It remains unresolved whether mavacamten permanently sequesters these myosin heads in the off state(s) or whether these heads can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by Ca 2+ , increased heart rate, stretch, and β-adrenergic (β-AR) stimulation, all known physiological inotropic effectors. At the molecular level, we show that, in presence of mavacamten, Ca 2+ increases myosin ATPase activity by shifting myosin heads from the reserve super-relaxed (SRX) state to the active disordered relaxed (DRX) state. At the myofilament level, both Ca 2+ and passive lengthening can shift ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments in the presence of mavacamten. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dt max, an index of inotropy, increased with heart rate in mavacamten treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are activable, at least partially, thus leading to preservation of cardiac reserve mechanisms.
Competing Interests: Competing interests C.Z and R.S are employees and own shares in Bristol Myers Squibb (formerly MyoKardia Inc.). S.N and S.G are former employees of Bristol Myers Squibb. C.dR. has a consulting relationship with Bristol Myers Squibb. S.M.M and M.P are partners in FilamenTech, Inc. and they provided the simulations at no cost. W.M and T.C.I consult for Edgewise Therapeutics Inc., but this activity has no relation to the current work. |
