[Immune mechanism of cardiac remodeling induced by antibodies against to the alpha1-adrenergic receptor].
OBJECTIVE
To study the effects of autoantibodies against alpha1-adrenergic receptor on the cardiac remodeling and relevant mechanism.


METHODS
Four-week-old male Wistar rats were immunized with synthesized second extracellular loop of alpha1-adrenergic receptor and raised for one year, with spontaneously hyperetensive rats (SHRs) and no-immunized Wistar rats of the same age as controls. Every one or two months blood was collected from the caudal vein to detect the level of serum antibodies to alpha1-adrenergic receptor by ELISA and the systolic blood pressure (SBP) and heart rate were measured. One year after the rats were killed and their hearts were taken out. The heart weight/body weight ratio, cardiac muscle cell cross-sectional area (CSA), interstitial collagen volume fraction (CVF) and the ratio of perivascular collagen area to vessel luminal area (PVCA) were calculated, the expression of alpha1-adrenergic receptor, c-fos and c-Jun in heart were measured by RT-PCR, Western blotting and immunohistochemistry.


RESULTS
During the experiment the blood pressure of the SHRs were significantly higher than those of the immunization group and normal control group (both P < 0.01) without significant difference between the 2 latter groups. The heart weight/body weight ratio, CSA, CVF and PVCA of the immobilization group were 3.32 mg/g +/- 0.25 mg/g, 231 microm(2) +/- 11 microm(2), 5.40% +/- 0.66% and 1.89 +/- 0.62 respectively, all significantly higher than those of the normal control group (3.06 mg/g +/- 0.25 mg/g, 197 microm(2) +/- 19 microm(2), 3.22% +/- 0.15% and 0.86 +/- 0.17 respectively), but still significantly lower than those of the SHR group. Since the second week after immunization, the titre of antibody against of the immunization group began increase, peaked in the second and third months, and then decreased slowly, and remained at a high level by the end of experiment. The titre of antibody was not correlated with blood pressure. Hypertrophy of cardiac muscle cells and increase of sedimentation of collagen in stroma were seen in the hearts of the immunization group. RT-PCR showed that the expression of alpha1D-adrenergic receptor mRNA of the immunization group was 0.55 +/- 0.01, significantly lower than that of the normal control group (0.88 +/- 0.08, P < 0.05); the expression of c-jun mRNA in the immunization group was 0.82 +/- 0.02, significantly higher than that in the normal control group (0.42 +/- 0.07, P < 0.05); and there were no significant differences in the expressions of heart alpha1A- and alpha1B-afrenergic receptors and c-fos mRNAs between these 2 groups. Western blotting showed that the expression of c-jun protein in the immunization group was 6.24 +/- 2.13, significantly higher than that in the normal control group (2.55 +/- 0.58, P < 0.05); and there were no significant differences in the expressions of c-fos andalpha1A-adrenergic receptor proteins between these 2 groups.


CONCLUSIONS
The antibodies against alpha1-adrenergic receptor up-regulates the expression of c-jun in cardiac muscle cells and interstitial fibroblast, which may be an immunologic mechanism of cardiac remodeling.
Zhou
Zi-hua
ZH
Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China.
Liao
Yu-hua
YH
Li
Liu-dong
LD
Wang
Bin
B
Wei
Fen
F
Wang
Min
M
Wei
Yu-miao
YM
D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001794:Blood Pressure / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000276:immunology*; D020257:Ventricular Remodeling / Q000276:immunology*
D001323:Autoantibodies; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1