DL-3-n-Butylphthalide Attenuates Myocardial Hypertrophy by Targeting Gasdermin D and Inhibiting Gasdermin D Mediated Inflammation

Overview

Journal Front Pharmacol

Date 2021 Jun 25

PMID 34168567

Citations 11

Authors

Bingjiang Han

JiaJun Xu

Xiaowen Shi

Zhanxiong Zheng

Fengjie Shi

Fenfen Jiang

Jibo Han

Affiliations

Soon will be listed here.

Abstract

Pressure overload leads to a hypertrophic milieu that produces deleterious cardiac dysfunction. Inflammation is a key pathophysiological mechanism underpinning myocardial hypertrophy. DL-3-n-butylphthalide (NBP), a neuroprotective agent, also has potent cardioprotective effects. In this study, the potential of NBP to antagonize myocardial hypertrophy was evaluated in C57BL/6 mice and in rat primary cardiomyocytes . In mice, NBP treatment reduced cardiac hypertrophy and dysfunction in a transverse aortic constriction (TAC)-induced pressure overload model. In angiotensin (Ang) II-challenged cardiomyocytes, NBP prevents cell size increases and inhibits gasdermin D (GSDMD)-mediated inflammation. Furthermore, overexpression of GSDMD-N reduced the protective effects of NBP against Ang II-induced changes. Using molecular docking and MD simulation, we found that the GSDMD-N protein may be a target of NBP. Our study shows that NBP attenuates myocardial hypertrophy by targeting GSDMD and inhibiting GSDMD-mediated inflammation.

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References

Welsh P, Woodward M, Rumley A, Lowe G . Associations of circulating TNFalpha and IL-18 with myocardial infarction and cardiovascular risk markers: the Glasgow Myocardial Infarction Study. Cytokine. 2009; 47(2):143-7. DOI: 10.1016/j.cyto.2009.06.002. View

Xie Y, Gao Y, Gao R, Yang W, Dong Z, Moses R . The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway. Cell Death Differ. 2020; 27(10):2952-2972. PMC: 7494903. DOI: 10.1038/s41418-020-0554-8. View

Tian X, He W, Yang R, Liu Y . Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis. J Biomed Sci. 2017; 24(1):38. PMC: 5471652. DOI: 10.1186/s12929-017-0345-9. View

Qiu H, Wu H, Ma J, Cao H, Huang L, Qiu W . DL-3-n-Butylphthalide reduces atrial fibrillation susceptibility by inhibiting atrial structural remodeling in rats with heart failure. Naunyn Schmiedebergs Arch Pharmacol. 2018; 391(3):323-334. DOI: 10.1007/s00210-017-1457-1. View

Han J, Ye S, Zou C, Chen T, Wang J, Li J . Angiotensin II Causes Biphasic STAT3 Activation Through TLR4 to Initiate Cardiac Remodeling. Hypertension. 2018; 72(6):1301-1311. DOI: 10.1161/HYPERTENSIONAHA.118.11860. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Huang L, Wang S, Ma F, Zhang Y, Peng Y, Xing C . From stroke to neurodegenerative diseases: The multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives. Pharmacol Res. 2018; 135:201-211. DOI: 10.1016/j.phrs.2018.08.007. View

Weber K, Brilla C . Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991; 83(6):1849-65. DOI: 10.1161/01.cir.83.6.1849. View

Long Y, Wang L, Li Z . SP1-induced SNHG14 aggravates hypertrophic response in in vitro model of cardiac hypertrophy via up-regulation of PCDH17. J Cell Mol Med. 2020; 24(13):7115-7126. PMC: 7339172. DOI: 10.1111/jcmm.15073. View

10.

Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H . Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015; 526(7575):660-5. DOI: 10.1038/nature15514. View

11.

Wang Q, Wu J, Zeng Y, Chen K, Wang C, Yang S . Pyroptosis: A pro-inflammatory type of cell death in cardiovascular disease. Clin Chim Acta. 2020; 510:62-72. DOI: 10.1016/j.cca.2020.06.044. View

12.

Yang F, Qin Y, Lv J, Wang Y, Che H, Chen X . Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis. 2018; 9(10):1000. PMC: 6155223. DOI: 10.1038/s41419-018-1029-4. View

13.

Han J, Shi X, Zheng Z, Zhang B, Shi F, Jiang L . Schisandrin B protects against angiotensin II-induced endotheliocyte deficits by targeting Keap1 and activating Nrf2 pathway. Drug Des Devel Ther. 2018; 12:3985-3997. PMC: 6255115. DOI: 10.2147/DDDT.S184245. View

14.

Ye S, Luo W, Khan Z, Wu G, Xuan L, Shan P . Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3. Circ Res. 2020; 126(8):1007-1023. DOI: 10.1161/CIRCRESAHA.119.315861. View

15.

Freund C, Schmidt-Ullrich R, Baurand A, Dunger S, Schneider W, Loser P . Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation. 2005; 111(18):2319-25. DOI: 10.1161/01.CIR.0000164237.58200.5A. View

16.

Wang Y, Li Y, Wang C, Ai J, Dong X, Huang H . L-3-n-Butylphthalide protects rats' cardiomyocytes from ischaemia/reperfusion-induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol (Oxf). 2013; 210(3):524-33. DOI: 10.1111/apha.12186. View

17.

Gaidt M, Hornung V . Pore formation by GSDMD is the effector mechanism of pyroptosis. EMBO J. 2016; 35(20):2167-2169. PMC: 5069554. DOI: 10.15252/embj.201695415. View

18.

Kayagaki N, Stowe I, Lee B, ORourke K, Anderson K, Warming S . Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015; 526(7575):666-71. DOI: 10.1038/nature15541. View

19.

Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M . Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J Am Coll Cardiol. 2018; 71(8):875-886. PMC: 5828038. DOI: 10.1016/j.jacc.2017.12.037. View

20.

Abdoulaye I, Guo Y . A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives. Biomed Res Int. 2017; 2016:5012341. PMC: 5178327. DOI: 10.1155/2016/5012341. View