Huoxue Qianyang Qutan recipe attenuates cardiac fibrosis by inhibiting the NLRP3 inflammasome signalling pathway in obese hypertensive rats

Abstract

Context: HuoXue QianYang QuTan Recipe (HQQR) is used to manage hypertension and cardiac remodelling, but the mechanism is elusive. Objective: To determine the mechanism of HQQR on obesity hypertension (OBH)-related myocardial fibrosis. Materials and methods: OBH models were prepared using spontaneously hypertensive rats (SHRs) and divided (n ¼ 6) into saline, low-dose (19.35 g/kg/d) HQQR, high-dose (38.7 g/kg/d) HQQR, and valsartan (30 mg/kg/d) groups for 10 weeks. Systolic blood pressure (SBP), and Lee's index were measured. Heart tissues were examined by histology. HQQR's effects were examined on cardiac fibroblasts (CFs) stimulated with angiotensin II and treated with HQQR, a caspase-1 inhibitor, siNLRP3, and oeNLRP3. Results: HQQR(H) reduced SBP (201.67 ± 21.00 vs. 169.00 ± 10.00), Lee's index (321.50 ± 3.87 vs. 314.58 ± 3.88), and left ventricle mass index (3.26 ± 0.27 vs. 2.71 ± 0.12) in vivo. HQQR reduced percentage of fibrosis area (18.99 ± 3.90 vs. 13.37 ± 3.39), IL-1b (10.07 ± 1.16 vs. 5.35 ± 1.29), and inhibited activation of NLRP3/caspase-1/IL-1b pathway. HQQR also inhibiting the proliferation (1.09 ± 0.02 vs. 0.84 ± 0.01), fibroblast to myofibroblast transition (14.74 ± 3.39 vs. 3.97 ± 0.53), and collagen deposition (Col I; 0.50 ± 0.02 vs. 0.27 ± 0.05 and Col III; 0.48 ± 0.21 vs. 0.26 ± 0.11) with different concentrations selected based on IC 50 in vitro (all ps < 0.05). NLRP3 interference further confirmed HQQR inhibiting NLRP3 inflammasome signalling. Conclusion: HQQR blunted cardiac fibrosis development in OBH and suppressed CFs proliferation by directly interfering with the NLRP3/caspase-1/IL-1b pathway.

The NLRP3 Inflammasome as a Novel Therapeutic Target for Cardiac Fibrosis

“… [ 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.…”

“… [ 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. …”

“… 57 Huoxue Qianyang Qutan recipe(HQQR) is a widely used Chinese herbal compound that can reduce blood pressure and improve lipid metabolism in obese hypertensive patients. 115 , 129 Recent findings have reported that HQQR could reduce cardiac fibrosis by inhibiting the NLRP3 inflammasome signaling pathway in obese hypertensive rats. 115 Emodin is a natural medicine that is effective for treating several chronic diseases; it has various pharmacological properties, including antioxidant, antimicrobial, antidiabetic, and immunosuppressive effects.…”

“… 115 , 129 Recent findings have reported that HQQR could reduce cardiac fibrosis by inhibiting the NLRP3 inflammasome signaling pathway in obese hypertensive rats. 115 Emodin is a natural medicine that is effective for treating several chronic diseases; it has various pharmacological properties, including antioxidant, antimicrobial, antidiabetic, and immunosuppressive effects. 130 A study by Xiao et al found that Emodin has anti-fibrotic action through the suppression of NLRP3 inflammasome activation induced by LPS.…”

Hypertension and its management in COVID-19 patients: The assorted view

“…Likewise, activated NF-κB signaling pathway in SARS-CoV-2 can induce activation of node-like receptor pyrin 3 (NLRP3) inflammasome, which is also stimulated by SARS-CoV-2 ORF3a protein, leading to the release of pro-inflammatory cytokines, mainly IL-1β [ 64 ]. Besides, NLRP3 inflammasome is also activated in obesity and hypertension due to underlying low-grade inflammatory status [ 65 , 66 ].…”