期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 1, 页码 229-243出版社
WILEY
DOI: 10.1111/jcmm.15937
关键词
adaptive immune system; auto‐ antibodies; autoimmunity; fibrosis; inflammation; isoprenaline; isoproterenol; myocardial infarction; type 2 myocardial infarction
资金
- British Heart Foundation [PG/16/93/32345]
- ISSF Wellcome Trust [105603/Z/14/Z]
- Medical Research Council (via King's College London) UKRMP Immunomodulation Hub [MR/L022699/1]
- Leducq Foundation: Trans-Atlantic Networks of Excellence in Cardiovascular Research
- Jackson Laboratory endowment [TJL-Rosenthal-01]
High dose isoproterenol can cause myocardial necrosis and trigger an adaptive immune response targeting the heart, leading to the development of autoimmune heart disease.
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ss-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
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