The NLRP3 Inflammasome as a Novel Therapeutic Target for Cardiac Fibrosis

Figures & data

Figure 1 Regulation and function of NLRP3 inflammasome during cardiac fibrosis. (A) Caspase-1 activated by NLRP3 as well as caspase-4,5 and caspase-11 in the non-classical pathway are able to trigger pyroptosis. (B) Caspase-1 cleaves and activates pro-IL-1β and pro-IL-18, and is released extracellularly through the GSDMD pore. (C) The priming stage of NLRP3 inflammasome. (D) and (E) TGF-β/Smad is an important pathway leading to cardiac fibrosis and NLRP3 is capable of regulating it.

Figure 2 NLRP3 inflammasome activation in cardiovascular diseases to promote cardiac fibrosis. Under pathological conditions, such as myocardial infarction, hypertension, and hyperglycemia, atrial fibrillation, NLRP3 inflammasome in cardiomyocytes and fibroblasts are activated, collaboratively promoting the inflammatory cascade and pyroptosis. The resultant cardiac inflammation triggers myofibroblast activation and cardiac fibrosis.

Table 1 Cardiac Fibrosis Therapies Targeting the NlRP3 Inflammasome Pathway

Drugs	Disease Model	Mechanism	References
MCC950	Coronary artery ligation	Binds noncovalently to NLRP3 and prevent ASC oligomerization	[54]
INF4E	Hearts isolated and perfused following myocardial I/R	Inhibits the NLRP3 ATPase activity	[93]
Tranilast	Coronary artery ligation	Supresses NLRP3 inflammasome and reduce collagen synthesis	[97]
OLT1177	Hearts isolated and perfused following myocardial I/R	Block ATPase activity of NLRP3 and inhibits NLRP3 oligomerization	[95]
Cy-09	Coronary artery ligation	Binds directly to the ATP-binding motif of the NACHT domain, inhibiting NLRP3 assembly and ATPase activity.	[94]
Hydrogen gas	Coronary artery ligation	Reduces the expression of NLRP3-mediated pyroptosis-related protein and allieviates collagen synthesis	[64]
Vincristine	ISO-induced cardiac fibrosis	Downregulated the colocalization of NLRP3 and ASC, and directly inhibited NLRP3 inflammasome activation	[107]
VX-765	Hearts isolated and perfused following myocardial I/R	Inhibits caspase-1 activation.	[112]
VX-740	Type II collagen-induced arthritis	Inhibits caspase-1 activation.	[111]
AC-YVAD-CMK	SHR	Inhibits caspase-1 activation.	[115]
Canakinumab	Patients with previous myocardial infarction	Specifically inhibits IL-1β	[118]
Anakinra	Patients with COVID-19	Antagonise human IL-1 receptor	[121]
Allopurinol	Fructose‐induced metabolic syndrome	Supresses NLRP3 inflammasome and alleviates cardiac fibrosis	[102]
Colchicine	Coronary artery ligation	Prevents P2X7-related pyroptosis and inhibits NLRP3 inflammasome assembly	[105]
Metformin	STZ-induced diabetes	Inhibits NLRP3 inflammasome and promotes autophagy.	[123]
Empagliflozin	TAC-induced HF	Inhibits NLRP3 inflammasome, and reduces pro-inflammatory cytokines.	[126]
Emodin	LPS-induced myocardial injury	Inhibits NLRP3 inflammasome-mediated pyroptosis and alleviates cardiac inflammation.	[131]
HQQR	SHR	Inhibits pyroptosis and alleviates cardiac fibrosis.	[115]
Triptolide	ISO-induced cardiac fibrosis	Inhibites NLRP3 inflammasome assembly and NLRP3-TGF-β1-Smad signaling pathway activation	[57]
Salvianolate	Coronary artery ligation	Inhbites TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways	[75]

Abbreviations: ASC, adaptor protein apoptosis‐associated speck‐like protein; NLRP3, nucleotide‐binding oligomerization domain leucine‐rich repeat and pyrin domain‐containing protein 3; SHR, spontaneously hypertensive rats; HF, heart failure; I/R, ischemic/reperfusion; COVID-19, Corona Virus Disease 2019; STZ, Streptozotocin; LPS, Lipopolysaccharide; TAC, transverse aortic constriction; ISO, isoproterenol; HQQR, Huoxue Qianyang Qutan recipe.

Gao R, Shi H, Chang S, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharmacol. 2019;74:105575.

 PubMed Web of Science ®Google Scholar

Mastrocola R, Penna C, Tullio F, et al. Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways. Oxid Med Cell Longev. 2016;2016:5271251.

 PubMed Web of Science ®Google Scholar

See F, Watanabe M, Kompa AR, et al. Early and delayed tranilast treatment reduces pathological fibrosis following myocardial infarction. Heart Lung Circ. 2013;22(2):122–132.

 PubMed Web of Science ®Google Scholar

Toldo S, Mauro AG, Cutter Z, et al. The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse. J Cardiovasc Pharmacol. 2019;73(4):215–222.

 PubMed Web of Science ®Google Scholar

Gao RF, Li X, Xiang HY, et al. The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice. Int Immunopharmacol. 2021;90:107133.

 PubMed Web of Science ®Google Scholar

Nie C, Zou R, Pan S, et al. Hydrogen gas inhalation ameliorates cardiac remodelling and fibrosis by regulating NLRP3 inflammasome in myocardial infarction rats. J Cell Mol Med. 2021;25(18):8997–9010.

 PubMed Web of Science ®Google Scholar

Ge C, Cheng Y, Fan Y, He Y. Vincristine attenuates cardiac fibrosis through the inhibition of NLRP3 inflammasome activation. Clin Sci (Lond). 2021;135(11):1409–1426.

 PubMed Web of Science ®Google Scholar

Audia JP, Yang XM, Crockett ES, et al. Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y(12) receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. Basic Res Cardiol. 2018;113(5):32.

 PubMed Web of Science ®Google Scholar

Ku GFP, Raybuck S, Harding M, Randle J. Selective Interleukin-1β Converting Enzyme (ICE/Caspase-1) Inhibition with Pralnacasan (HMR 3480/VX-740) Reduces Inflammation and Joint Destruction in Murine Type II Collagen-Induced Arthritis (CIA). Arthritis Rheumatism. 2001;44(9):S241.

 PubMedGoogle Scholar

Lu B, Xie J, Fu D, et al. Huoxue Qianyang Qutan recipe attenuates cardiac fibrosis by inhibiting the NLRP3 inflammasome signalling pathway in obese hypertensive rats. Pharm Biol. 2021;59(1):1045–1057.

 PubMed Web of Science ®Google Scholar

Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119–1131.

 PubMed Web of Science ®Google Scholar

Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2(6):e325–e331.

 PubMedGoogle Scholar

Kang LL, Zhang DM, Ma CH, et al. Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation. Sci Rep. 2016;6:27460.

 PubMed Web of Science ®Google Scholar

Fujisue K, Sugamura K, Kurokawa H, et al. Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction. Circ J. 2017;81(8):1174–1182.

 PubMed Web of Science ®Google Scholar

Yang F, Qin Y, Wang Y, et al. Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy. Int J Biol Sci. 2019;15(5):1010–1019.

 PubMed Web of Science ®Google Scholar

Byrne NJ, Matsumura N, Maayah ZH, et al. Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure. Circ Heart Fail. 2020;13(1):e006277.

 PubMed Web of Science ®Google Scholar

Dai S, Ye B, Chen L, Hong G, Zhao G, Lu Z. Emodin alleviates LPS-induced myocardial injury through inhibition of NLRP3 inflammasome activation. Phytother Res. 2021;35(9):5203–5213.

 PubMed Web of Science ®Google Scholar

Pan XC, Liu Y, Cen YY, et al. Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis. Int J Mol Sci. 2019;20(2):849.

 PubMed Web of Science ®Google Scholar

Qiu H, Liu W, Lan T, et al. Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats. Phytomedicine. 2018;51:255–265.

 PubMed Web of Science ®Google Scholar