Deletion of Irisin Mitigates HDAC4 Inhibitor-Elicited Protective Effect in Hemorrhage

Abstract

Introduction: Histone deacetylate inhibition contributes critically to modulating insulin resistance and cardiovascular function. It remains unknown whether inhibition of specific HDAC isoform 4 could improve cardiac function and attenuates inflammatory response and whether HDAC4 inhibition-induced protection is related to irisin. The objective of this study is to investigate whether HDAC4 inhibition induced protective effect against hemorrhage-induced detrimental effects would be diminished by deletion of irisin. Method: Irisin knockout (irisin−/−) mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) Wild type (WT)+Hemorrhage (control) (N=7): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) NVS-HD-1+Hemorrhage (n=7): The same as the group I except that NVS-HD1, a selective HDAC inhibitor (3mg/kg) was infused during resuscitation; III) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; IV) NVS-HD-1 + Irisin−/−+Hemorrhage (n=6): The same as the groups III except that NVS-HD-1 was given to Irisin −/− during resuscitation. Myocardial function and hemodynamics were assessed using echocardiography and femoral artery catheterization, respectively. Cytokine releases from serum were measured using Enzyme-linked immunosorbent assay (ELISA). Histological assessment was performed to determine tissue damage in both myocardium and skeletal muscles. TUNEL was carried out to assess apoptotic signal in tissues. Results: As compared to control group, HDAC4 inhibitor significantly improved the cardiac function and recovery of hemodynamics, which was associated with the decreased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were mitigated by inhibition of HDAC4. However, HDAC4 inhibitor-induced myocardial protection and suppression of inflammation against hemorrhage was lost by genetic deletion of irisin. Conclusion: Selective inhibition of HDAC4 produced protective effects with an improvement in myocardial function and attenuation of inflammation against hemorrhage, which is dependent on irisin. The work is supported by the National Institute of General Medical Sciences (R01GM 141339), United States; the National Heart, Lung, and Blood Institute Grants (R01 HL089405), United States. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.