Relations Of Autoantibodies Against β₃-Adrenoceptor To Heart Failure

Autoimmune mechanisms have been proposed to participate in the pathogenesis of chronic heart failure(CHF).In this study,we examined the immunoglobulin fractions of sera from healthy subjects and patients with chronic heart failure suffering from dilated cardiomyopathy (DCM),coronary artery disease(CAD),rheumatic heart disease(RHD) and hypertensive heart disease(HHD) for the presence of autoantibodies against the three extracellular loops ofβ₃-adrenoceptor.Autoantibodies against the three extracellular loops ofβ₃-adrenoceptor(anti-β₃-EC_â… ,anti-β₃-EC_â…¡and anti-β₃-EC_â…¢) were all detected in the sera of patients with heart failure and healthy subjects.However,among them the occurrence frequency and level of anti-β₃-EC_â…¡were the highest and by far higher than those of anti-β₃-EC_â… and anti-β₃-EC_â…¢.In addition,the frequency and level of anti-β₃-EC_â…¡in patients with heart failure(resulted mainly from DCM and CAD) were significantly higher than those in healthy subjects.Consequently,it is rational to assume that anti-β₃-EC_â…¡is an important functional antibody involved in the pathogenesis of heart failure.The frequency of anti-β₃-EC_â… in patients with DCM was also higher than that in healthy subjects but with fairly low titre level,while no statistical differences in both frequency and level of anti-β₃-EC_â…¢were seen between patients with CHF and healthy subjects.The effects of anti-β₃-EC_â…¡on the cardiac function level of the failing heart were also analyzed.It was suggested that anti-β₃-EC_â…¡might play a functional protective role in the development of heart failure. Experimental rat models with aortic banding were used to study the relations of development of heart failure to the genesis of serum autoantibodies to cardiacβ₃-adrenoceptor. 120 Wistar rats were divided into 2 groups:aortic banding group(n=80) and sham operated control group(n=40).On the basis of cardiac anatomic measurements,light microscopic examination,as well as myocardial collagen staining,it was shown that the experimental models underwent remarkable myocardial remodeling.During this period,the level of the autoantibodies againstβ₃-adrenoceptor in experimental group was exceedingly increased as compared with pre-treatment level accompanied by increased expression of cardiacβ₃-adrenoceptor protein, while in control group no significant changes were observed.These results suggest that the up-regulation of myocardialβ₃AR might be a crucial factor involving in the stimulation of genesis ofβ₃AR autoantibody during the course of heart failure.Moreover,the antoantibody againstβ₃AR exhibited the time course of occurrence,maintenance and disappearance,which is consistent with the trends of antibody producing ability alternation,confirming that the induction ofβ₃AR autoantoantibody is independent on the quantity of B lymphocytes,but is mainly regulated by functional statues of immune system.This might be an important form that immunological mechanism involved in the pathophysiological mechanisms of some caridac diseases.Furthermore,the mechanisms ofβ₃AR autoantoantibody need to be explored in the future. An experiment model of cardiomyopathy was created by immunizing rats for 6 months with synthetic peptides corresponding to the sequence of the second extracellular loop of bothβ₃-adrenoceptor.Twenty rats were used and divided into two groups:a control group(n=8) and a group immunized with the peptide corresponding to theβ₃-adrenoceptor(β₃ immunity group, n=12).In the sera fromβ₃ immunized rats,high-level of anti-β₃-adrenoceptor antibodies were found throughout the study period,but noly a low level of antibodies were found in the sera from some control rats or in the preimmune sera of some immunized rats.At 3 and 6 months after immunization,the left ventricular systolic and diastolic function in immunized group were slightly but not significantly enhanced than that of in the control group,and morphological examination of the hearts ofβ₃ immunized rats demonstrated no obvious alterations.Moreover, compared with the corresponding controls,the myocardialβ₃-adrenoceptor density and the concentration of myocardial total NO of immunized rats displayed a slightly up-regulation and the myocardial eNOS and cGMP concentrations of immunized rats displayed significantly increased after 3 and 6 months of immunization.These results suggested that tha autoantibodies againstβ₃-adrenoceptor maybe transducte signal through eNOS-NO-cGMP pathway,however, immunization by peptide corresponding to the target sequences for anti-β₃-adrenoceptor antibodies for 6 months did not induces obviously morphological and functional changed in the heart.