Pioglitazone Protects Against Hypoxia-Induced Cardiomyocyte Apoptosis Through Inhibiting NLRP3/Caspase-1 Pathway <i>in vivo</i> and <i>in vitro</i>

Abstract

This study aims to explore the underlying mechanisms of how Pioglitazone (Pio) affects myocardial ischemia-reperfusion (I/R) injury. In this study, after pretreatment of Pio, the pathologic change of myocardial tissues was measured via hematoxylin and eosin staining. The release of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and nitric oxide (NO) were measured. The cardiomyocyte apoptosis was detected via TUNEL assay and flow cytometry assay. The mitochondrial membrane potential (ΔΨm) was estimated using the JC-1 probe. The release of cytochrome c in mitochondria and the translocation of cytochrome c in the cytosol were measured using western blot. Additionally, apoptosis-associated molecules and NOD-like receptor pyrin domain containing-3 (NLRP3)/caspase-1 pathway-related molecules were measured using western blot, quantitative real-time-polymerase chain reaction, and immunofluorescence staining. Results showed that the pretreatment of Pio significantly decreased myocardial tissue damage. Pio pretreatment inhibited the release of creatine kinase and LDH but promoted NO release in serum and H9c2 cell supernatants. Moreover, the pretreatment of Pio notably alleviated cardiomyocyte apoptosis. Pio pretreatment also maintained the mitochondrial membrane potential and prevented cytochrome c release in H/R-induced cardiomyocytes. Additionally, we confirmed that Pio pretreatment inhibited cardiomyocyte apoptosis via repressing the NLRP3/caspase-1 pathway. In conclusion, our study demonstrated that Pio could inhibit myocardial I/R injury and cardiomyocyte apoptosis by inhibiting the activation of the NLRP3/caspase-1 signaling pathway.

Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming

“…Of note, several publications previously suggested that pioglitazone and PPAR‐γ prevented NLRP3 inflammasome activation. Pioglitazone inhibited the expression levels of NLRP3 inflammasome components, including NLRP3, ASC, procaspase‐1, and pro‐IL‐1β in the renal cortex of apoE‐deficient mice [35] and in rat H9c2 cardiomyocyte cells upon ischemia–reperfusion stimulation [36]. Rosiglitazone, another PPAR‐γ agonist, inhibited angiotensin II‐induced NLRP3 inflammasome components in mouse C2C12 myotube cells but did not affect the basal levels [37].…”

Modified Linggui Zhugan Decoction protects against ventricular remodeling through ameliorating mitochondrial damage in post-myocardial infarction rats

“…The NLRP3 inflammasome, a multiprotein binding compound consisting of NLRP3, connector protein ASC and effector protein pro-caspase-1, is activated under stress and plays an important role in cardiac fibrosis ( 69 – 71 ). The inflammasome exerts an inflammatory effect by regulating the release of proinflammatory cytokines including IL-1β and IL-18, contributing to cardiomyocyte apoptosis and dysfunction, and leading to ventricular remodeling and heart failure ( 69 , 72 , 73 ). NFκB is a master regulator of inflammatory gene expression and is activated in a variety of cardiac diseases, including congestive heart failure and cardiac hypertrophy ( 74 ).…”