Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling

Liu, Libao; Huang, Shuai; Du, Yingzhen; Zhou, Hao; Zhang, Kai; He, Jinyuan

doi:10.7150/ijbs.84426



Theranostics

International Journal of Medical Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

Global reach, higher impact

Full Text | PDF

Int J Biol Sci 2023; 19(11):3428-3440. doi:10.7150/ijbs.84426 This issue Cite

Research Paper

Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling

Libao Liu^1*, Shuai Huang^1*, Yingzhen Du^2✉, Hao Zhou³, Kai Zhang^1✉, Jinyuan He^1✉

1. Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat sen University, Guangzhou, Guangdong, 510620, China.
2. The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China.
3. School of Medicine, University of Rochester Medical Center Rochester, Rochester, NY 14642, United States.
*The first four authors contributed equally to this article.

Citation:

Liu L, Huang S, Du Y, Zhou H, Zhang K, He J. Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling. Int J Biol Sci 2023; 19(11):3428-3440. doi:10.7150/ijbs.84426. https://www.ijbs.com/v19p3428.htm

Other styles

Abstract

Large tumor suppressor kinase 2 (Lats2) is a member of the Hippo pathway, a critical regulator of organ size. Since Lats2 activity may trigger mitochondrial dysfunction, a key pathogenic factor in acute myocardial infarction (AMI), this study sought to investigate whether Lats2 deletion confers cardioprotection in AMI. AMI was induced in cardiomyocyte-specific Lats2 knockout (Lats2^Cko) and control (Lats2^flox) mice. Twenty-eight days after AMI surgery, myocardial performance and mitochondrial homeostasis were impaired in Lats2^flox mice. In contrast, Lats2^Cko mice exhibited markedly preserved cardiac structure and contraction/relaxation activity, decreased fibrosis, reduced circulating cardiac injury biomarker levels, and enhanced cardiomyocyte viability. Consistent with these findings, siRNA-mediated Lats2 silencing sustained mitochondrial respiration and inhibited apoptosis in hypoxia-treated HL-1 cardiomyocytes. Notably, Lats2 deficiency inhibited AMI/hypoxia-related mitochondrial fission and inactivated STING/p65 signaling by preventing hypoxia-induced release of mtDNA into the cytosol. Accordingly, pharmacological reactivation of STING signaling abolished the cardioprotective effects of Lats2 ablation. Those data suggest that AMI-induced Lats2 upregulation is associated with impaired cardiomyocyte viability and function resulting from enhanced mitochondrial fission, mtDNA release, and STING/p65 pathway activation.

Keywords: Acute myocardial infarction, Lats2, mitochondrial fission, mtDNA, STING

Citation styles

APA

Liu, L., Huang, S., Du, Y., Zhou, H., Zhang, K., He, J. (2023). Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling. International Journal of Biological Sciences, 19(11), 3428-3440. https://doi.org/10.7150/ijbs.84426.

ACS

Liu, L.; Huang, S.; Du, Y.; Zhou, H.; Zhang, K.; He, J. Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling. Int. J. Biol. Sci. 2023, 19 (11), 3428-3440. DOI: 10.7150/ijbs.84426.

NLM

CSE

Liu L, Huang S, Du Y, Zhou H, Zhang K, He J. 2023. Lats2 deficiency protects the heart against myocardial infarction by reducing inflammation and inhibiting mitochondrial fission and STING/p65 signaling. Int J Biol Sci. 19(11):3428-3440.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.