Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells

Abstract

Purpose Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Methods Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. Results PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. Conclusion PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Graphical abstract Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

Pyrroloquinoline quinone modulates YAP-related anti-ferroptotic activity to protect against myocardial hypertrophy

“…Therefore, these series of properties make PQQ more valuable for research than other compounds. PQQ has previously been shown to exert cardioprotective activity in the context of myocardial infarction ( Zhu et al, 2004 ), diabetic cardiomyopathy ( Qu et al, 2022 ), lipid abnormalities ( Bauerly et al, 2011 ), and COVID-19 mRNA vaccine-related cardiac inflammation ( Boretti, 2022 ). Whether PQQ can alleviate pathological myocardial hypertrophy via anti-ferroptotic mechanisms, however, has not been previously assessed.…”

“…PQQ (at a dose equivalent to previous studies ( Qu et al, 2022 ); 40 mg/kg in PBS) or an equal volume of PBS were administered to mice via gavage every other day for a 6-week period beginning on day 2 post-surgery. The survival rate of mice after TAC remained above 80% among all groups and did not differ significantly.…”

“…Pyrroloquinoline quinone (PQQ) is a natural water-soluble redox coenzyme that is found throughout plant and animal tissues, serving as an essential nutrient in mammals with purported cardioprotective activity ( Akagawa et al, 2016 ). Moreover, PQQ has been shown to exhibit antioxidant activity in a rat model of diabetic nephropathy ( Zhang et al, 2020 ), and to protect against diabetic cardiomyopathy via the inhibition of scorched death signaling activity ( Qu et al, 2022 ). Nehra et al (2017) further developed a PQQ- and curcumin-containing nano-curcumin formulation capable of reducing the severity of hypoxia-induced ventricular myocyte hypertrophy and injury.…”

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

“…It was shown that pinocembrin can inhibit pyroptosis by activation of Nrf2/Sirt3 signaling pathway, LVEF, LVFS, LVIDd, LVID, and myocardial fibrosis were improved, and the expressions of LDH, CK-MB, IL-1β, and IL-18 were reduced ( 111 ). Pyrroloquinoline quinone inhibited ROS and NF-κB activation inhibited NLRP3 inflammasome and Caspase-1, IL-1β and IL-18 expression, and improved myocardial hypertrophy and cardiac fibrosis ( 112 ). Ranolazine treatment of diabetic cardiac fibrosis inhibited pyroptosis and collagen deposition by upregulating miR-135b ( 71 ).…”

Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications

“…Many drugs have been demonstrated to have some effects against pyroptosis (e.g., metformin [ 91 ], exendin-4 [ 92 ], pyrroloquinoline quinone (PQQ) [ 93 ], and skimming) [ 94 ]. A natural coumarin derivative has been found to protect against experimental DC by inhibiting pyroptosis in cardiomyocytes [ 94 ].…”