Abstract
BackgroundPrevious studies showed that autoantibodies (M2-AA) against the second extracellular loop of M2 muscarinic receptor (M2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M2-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M2 receptor binding characteristics in rats long-term stimulated with M2-AA in vivo.MethodsM2-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M2AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M2 receptor binding characteristics were determined by radioactive ligand binding assay.ResultsAfter immunization for 12 months, compared with vehicle group, M2AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M2AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M2 receptor maximum binding capacity (Bmax) of the M2AChR-el2-immunized rats significantly decreased, while the M2 receptor dissociation constant (Kd) was increased.ConclusionsOur study suggested that long-term stimulation with M2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction. Mitochondrial damage and the down-regulation of M2 receptor density and affinity may be involved in the process.
Highlights
Idiopathic dilated cardiomyopathy (DCM), a refractory and primary myocardial disease, is a major cause of death in patients with heart failure
Our study suggested that long-term stimulation with M2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction
Mitochondrial damage and the downregulation of M2 receptor density and affinity may be involved in the process
Summary
Idiopathic dilated cardiomyopathy (DCM), a refractory and primary myocardial disease, is a major cause of death in patients with heart failure. It has long been known that there are high titers of autoantibodies against the second extracellular loop of the M2 muscarinic receptor (M2-AA) in sera of patients with DCM [2]. A previous study demonstrated that M2-AA could recognize the second extracellular loop of the M2 muscarinic receptor (M2AChR-el2) and stimulate the muscarinic receptor on rats’ heart membrane [4]. Previous studies showed that autoantibodies (M2-AA) against the second extracellular loop of M2 muscarinic receptor (M2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M2 receptor binding characteristics in rats long-term stimulated with M2-AA in vivo
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
