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. 2024 Oct 28;68(4):4122.
doi: 10.4081/ejh.2024.4122.

Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction

Jinshuang Li  1 , Dawei Xu  2 , Ce Shi  3 , Chunqi Cheng  4 , Ziheng Xu  1 , Xingjuan Gao  1 , Yong Cheng  4
Affiliations

Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction

Jinshuang Li et al. Eur J Histochem. .

Abstract

Heart failure with preserved ejection fraction (HFpEF), a complex disease that is increasingly prevalent due to population aging, pose significant challenges in its treatment. The present study utilized the HFpEF rat model and H9C2 cells as research subjects to thoroughly investigate the potential mechanisms of alarin in protecting cardiac function in HFpEF. The study shows that under HFpEF conditions, oxidative stress significantly increases, leading to myocardial structural damage and dysfunction of calcium ion channels, which ultimately impairs diastolic function. Alarin, through its interaction with NADPH oxidase 1 (NOX1), effectively alleviates oxidative stress and modulates the activities of type 2 ryanodine receptor (RyR2) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), thereby facilitating the restoration of Ca2+ homeostasis and significantly improving cardiac function in the HFpEF model. This research not only uncovers the cardioprotective effects of alarin and its underlying molecular mechanisms but also provides new insights and potential therapeutic targets for HFpEF treatment strategies, suggesting a promising future for alarin and related therapies in the management of this debilitating condition.

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Figures

Figure 1.
Figure 1.
Alarin improved cardiac function in HFpEF rats. A) Echocardiographic examination of the EF, LA, and E/e' in HFpEF rats (n=5). B) Observation of H&E-stained cardiac tissue sections (n=3). C) Observation of Masson's trichrome-stained cardiac tissue sections (n=3). The results are expressed as mean ± SEM. EF, ejection fraction; LA, left atrium area; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 indicate statistically significant difference versus the model group; scale bars: 100 μm.
Figure 2.
Figure 2.
Alarin alleviated the oxidative stress in HFpEF. A) Content of ROS and 8-OHdG in myocardial tissue of HFpEF rats were assessed by ELISA. B) Viability of H9C2 cells in the different groups. C) The content of 8-OHdG in H9C2 cells was assessed by ELISA. D) Relative level of ROS detected by DCF probe in H9C2 cells; scale bars: 100 μm. The results are expressed as mean ± SEM; n=3 for each group. ROS, reactive oxygen species; 8-OHdG, 8-hydroxy-2'-deoxyguanosine; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 indicate statistically significant difference versus the model group (A,B,D).
Figure 3.
Figure 3.
Administering alarin could improve the expression level of alarin in HFpEF rats and H9C2 cells. A) Immunohistochemistry was used to identify alarin expression in myocardial tissue; scale bar: 100 μm. B) Detection of alarin in the supernatant of H9C2 cells. C) Expression level of alarin in H9C2 cells. The results are expressed as mean ± SEM; n=3 for each group. ****p<0.0001; ns, not significant.
Figure 4.
Figure 4.
Alarin can interact with NOX1 and suppress the expression of NOX1 in HFpEF rats and H9C2 cells. A) Identification of the interaction between alarin and NOX1 by Co-IP. B) Expression level of NOX1 expression in myocardial tissue; scale bar: 100 μm. C) The expression level of NOX1 in H9C2 cells. The results are expressed as mean ± SEM; n=3 for each group. ***p<0.001; ****p<0.0001.
Figure 5.
Figure 5.
Alarin exhibits the capacity to regulate the expression of RyR2 and SERCA2 in HFpEF. A) Expression level of RyR2 and SERCA2 in myocardial tissue. B) The expression level of RyR2 and SERCA2 in H9C2 cells. The results are expressed as mean ± SEM; n=3 for each group. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
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References

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Grants and funding

Funding: this work was supported by Suqian Sci&Tech Program (Grant No. K202218), Suqian Traditional Chinese Medicine Technology Program (Grant No. HD202214) and Xuzhou Medical University Affiliated Hospital Sci&Tech Program (Grant No. XYFM202325).