title: Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  M2-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.
  
  
  RESULTS
  After 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.
  
  
  CONCLUSIONS
  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 down-regulation of M2 receptor density and affinity may be involved in the process.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China; The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100069, P. R. China.
authors.forename: Suli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Zhongmei
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China; The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100069, P. R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Lv
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China; Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China; Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Capital Medical University, Beijing, 100069, P. R. China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000032:analysis / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D043585:Receptor, Muscarinic M2