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Chronic β-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis

Acta Pharmacologica Sinica volume 44, pages 1989–2003 (2023)Cite this article

Abstract

Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1β, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac β1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective βAR blocker carvedilol (2.5 mg·kg−1·d−1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg−1·d−1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent β-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.

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Fig. 1: CIA rats successively develop cardiac diastolic and systolic dysfunction.
Fig. 2: The development of heart dysfunction in CIA rats deviated from the process of joint and systemic inflammation.
Fig. 3: Cardiomyopathy in CIA rats is independent of AS.
Fig. 4: Increased β-adrenergic stress was found to accompany heart function impairment in CIA rats.
Fig. 5: Blocking β1AR activation by carvedilol or inhibiting GRK2 specifically rescued heart function in mice with CIA.
Fig. 6: Carvedilol or paroxetine treatment successfully improved the morphology and adrenergic response of heart from CIA mice.
Fig. 7: Schematic diagram of the mechanism of RA-induced heart failure.

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Funding

This work is supported by the National Natural Science Foundation of China (81973314, 81202541, and 81973332); the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars (1808085J28); Collaborative Innovation Project of Key Scientific Research Platform in Anhui Universities (GXXT-2020-066); Anhui Provincial Key R&D Programs (2022e07020042); Program for Upgrading Scientific Research Level of Anhui Medical University (2019xkjT008); and Academic Funding for Top-notch Talents in University Disciplines (Majors) of Anhui Province (gxbjZD2021047).

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Author notes

  1. These authors contributed equally: Zhen-duo Zhu, Mei Zhang, Zhen Wang

Authors and Affiliations

  1. The Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education; Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China

    Zhen-duo Zhu, Mei Zhang, Zhen Wang, Chun-ru Jiang, Hui-juan Cheng, Qiu-yun Guan, Tian-tian Su, Man-man Wang, Wei Wei & Qing-tong Wang

  2. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China

    Mei Zhang

  3. Department of Emergency Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230001, China

    Chong-jian Huang & Yong-sheng Han

  4. Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Chong-jian Huang & Yong-sheng Han

  5. Department of Pathology, Anhui Medical University, Hefei, 230032, China

    Yi Gao

  6. College of Pharmacy, Anhui University of Chinese Medicine, Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Hefei, 230038, China

    Hong-fei Wu

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Contributions

ZDZ, MZ, ZW, YSH, and QTW conceptualised the project and design of the research; ZDZ, MZ, ZW, CJH, CRJ, HJC, QYG, TTS, MMW, and HFW performed the experiments; YG performed the pathological analysis. YSH collected biological samples and clinical data. ZDZ, MZ, ZW, and QTW analysed the data; ZDZ and QTW wrote the original paper; ZDZ, HFW, WW, YSH, and QTW reviewed and edited the paper. All authors approved the final version of the paper.

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Correspondence to Yong-sheng Han or Qing-tong Wang.

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Zhu, Zd., Zhang, M., Wang, Z. et al. Chronic β-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis. Acta Pharmacol Sin 44, 1989–2003 (2023). https://doi.org/10.1038/s41401-023-01099-2

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