Upregulation of CIRP by its agonist prevents the development of heart failure in myocardial infarction rats
- BMC Cardiovasc Disord. 2024 Mar 27;24(1):185. doi: 10.1186/s12872-024-03852-9.
- 1. Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China.
- 2. Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.
- 3. Hubei Key Laboratory of Cardiology, Wuhan, 430060, China.
- 4. The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, China.
- 5. The Second Affiliated Hospital, Key laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang Medical School, University of South China, Hengyang, 421001, China.
- 6. Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, University of South China, Hengyang, 421001, China.
- 7. The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, China. [email protected].
- 8. The Second Affiliated Hospital, Key laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang Medical School, University of South China, Hengyang, 421001, China. [email protected].
- 9. Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, University of South China, Hengyang, 421001, China. [email protected].
- 10. Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China. [email protected].
- 11. Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China. [email protected].
- 12. Hubei Key Laboratory of Cardiology, Wuhan, 430060, China. [email protected].
- # Contributed equally.
Background: Downregulated expression of cold-inducible RNA binding protein (CIRP), a stress-response protein, has been demonstrated in the hearts of patients with heart failure (HF). However, whether CIRP plays a critical role in the pathogenesis of HF remains unknown. Zr17-2 is a recently identified CIRP agonist, which can enhance the expression of CIRP in hearts. Herein, we evaluated the effects of zr17-2 on the development of HF in a rat model of myocardial infarction (MI).
Methods: Male SD rats were pretreated with CIRP agonist zr17-2 or vehicle saline for 6 consecutive days, followed by MI induction. 1-week post-MI, cardiac function, and structural and molecular changes were determined by echocardiography and Molecular Biology methods.
Results: Excitingly, we found that pretreatment with zr17-2 significantly attenuated MI-induced cardiac dysfunction and dilation, coupled with reduced infarction size and cardiac remodeling. In addition, increased inflammatory response in the peri-infarcted heart including macrophage infiltration and the expression of inflammatory genes were all significantly decreased by zr17-2 pretreatment, suggesting an anti-inflammatory effect of zr17-2. Moreover, zr17-2 pretreatment also upregulated the antioxidant genes (e.g. NQO-1, Nrf2, and HO-1) level in the hearts. In isolated cultured cardiomyocytes, pretreatment with zr17-2 markedly attenuated cell injury and Apoptosis induced by oxidative injury, along with elevation of Nrf2-related antioxidant genes and CIRP. However, silencing CIRP abolished zr17-2's antioxidant effects against oxidative injury, confirming that zr17-2's role is dependent on CIRP.
Conclusion: Collectively, our study suggests CIRP plays a crucial role in the development of HF and a beneficial effect of CIRP agonist in preventing MI-induced HF, possibly via anti-inflammatory and anti-oxidant pathways.
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