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Phloretin ameliorates heart function after myocardial infarction via NLRP3/Caspase-1/IL-1β signaling
Bin Li1, Liao Xu1, Jiangwen Liu1
1Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
Insights
Phloretin, an anti-inflammatory agent, was found to inhibit the NLRP3/Caspase-1/IL-1β pathway after myocardial infarction (MI) in rats. This intervention improved cardiac function, reduced fibrosis, and prevented arrhythmias and heart failure.
Area of Science:
- Cardiovascular Research
- Inflammation and Immunology
- Pharmacology
Background:
- Inflammation plays a critical role in cardiac remodeling post-myocardial infarction (MI), impacting both pump function and electrical conduction.
- Phloretin is known to inhibit the NLRP3/Caspase-1/IL-1β inflammatory pathway, but its specific effects on cardiac function after MI were not well understood.
Purpose of the Study:
- To investigate the therapeutic potential of Phloretin in mitigating structural and electrical remodeling following myocardial infarction (MI) in a rat model.
- To elucidate the mechanisms by which Phloretin influences cardiac electrophysiology and function after MI.
Main Methods:
- A rat model of MI was established by ligating the left anterior descending coronary artery, with groups receiving either Phloretin or a placebo.
- Cardiac electrophysiological properties (ERP, APD90, VF incidence), echocardiographic parameters (LVEF, LVFS), cardiac fibrosis, and protein expression (NLRP3, Caspase-1, IL-1β, Cx43) were assessed.
- In vitro studies using H9c2 cells under hypoxic conditions further validated the effects of Phloretin on the NLRP3 pathway.
Main Results:
- Phloretin administration significantly inhibited the NLRP3/Caspase-1/IL-1β pathway, leading to increased Connexin43 (Cx43) expression by limiting p38 phosphorylation.
- This mechanism reduced susceptibility to ventricular arrhythmias (VAs) and attenuated cardiac fibrosis, thereby preventing heart failure (HF).
- In vitro results corroborated the inhibitory effects of Phloretin on the key inflammatory pathway.
Conclusions:
- Phloretin demonstrates a protective effect against myocardial infarction by suppressing the NLRP3/Caspase-1/IL-1β pathway.
- This suppression reverses detrimental structural and electrical remodeling, preventing ventricular arrhythmias and heart failure post-MI.
- Phloretin holds promise as a therapeutic agent for managing complications arising from myocardial infarction.
Objectives/Aims:
Inflammation is crucial in structural and electrical remodeling after myocardial infarction (MI), affecting cardiac pump function and conduction pathways. Phloretin possesses an anti-inflammation role by inhibiting the NLRP3/Caspase-1/IL-1β pathway. However, the effects of Phloretin on cardiac contractile and electrical conduction function after MI remained unclear. Therefore, we aimed to investigate the potential role of Phloretin in a rat model of MI.
Methods:
Rats were assigned into four groups: Sham, Sham+Phloretin, MI and MI+Phloretin, with ad libitum food and water. In the MI and MI+Phloretin groups, the left anterior descending coronary artery was occluded for 4 weeks, while the Sham and Sham+Phloretin groups received sham operation. The Sham+Phloretin group and the MI+Phloretin group received oral administration of Phloretin. In vitro, H9c2 cells were subjected to hypoxic conditions to simulate an MI model, with Phloretin for 24 h. Cardiac electrophysiological properties were assessed following MI, including the effective refractory period (ERP), action potential duration (APD)90 and ventricular fibrillation (VF) incidence. Echocardiography evaluated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) to assess cardiac function. Serum type B natriuretic peptide (BNP) level was applied to evaluate the degree of Heart failure (HF). The fibrosis area and severity were assessed by Masson staining and protein expression levels of collagen 3, collagen 1, TGF-β and α-SMA. Western blot analysis estimated the protein expression levels of NLRP3, Pro Caspase-1, Caspase-1, ASC, IL-18, IL-1β, pp38, p38, and Connexin43(Cx43) to elucidate the influence of inflammation on electrical remodeling after MI.
Results:
Our findings demonstrate that Phloretin inhibits the NLRP3/Caspase-1/IL-1β pathway, leading to the upregulation of Cx43 by limiting p38 phosphorylation, which further decreases susceptibility to ventricular arrhythmias (VAs). Additionally, Phloretin attenuated fibrosis by inhibiting inflammation to prevent HF. In vitro experiments also provided strong evidence supporting the inhibitory effects of Phloretin on the NLRP3/Caspase-1/IL-1β pathway.
Conclusion:
Our results suggest that Phloretin could suppress the NLRP3/Caspase-1/IL-1β pathway to reverse structural and electrical remodeling after MI to prevent the occurrence of VAs and HF.
