Urolithin A protects severe acute pancreatitis‐associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes

Abstract

Severe acute pancreatitis (SAP) often develops into acute cardiac injury (ACI), contributing to the high mortality of SAP. Urolithin A (UA; 3,8‐dihydroxy‐6H‐dibenzopyran‐6‐one), a natural polyphenolic compound, has been extensively studied and shown to possess significant anti‐inflammatory effects. Nevertheless, the specific effects of UA in SAP‐associated acute cardiac injury (SACI) have not been definitively elucidated. Here, we investigated the therapeutic role and mechanisms of UA in SACI using transcriptomics and untargeted metabolomics analyses in a mouse model of SACI and in vitro studies. SACI resulted in severely damaged pancreatic and cardiac tissues with myocardial mitochondrial dysfunction and mitochondrial metabolism disorders. UA significantly reduced the levels of lipase, amylase and inflammatory factors, attenuated pathological damage to pancreatic and cardiac tissues, and reduced myocardial cell apoptosis and oxidative stress in SACI. Moreover, UA increased mitochondrial membrane potential and adenosine triphosphate production and restored mitochondrial metabolism, but the efficacy of UA was weakened by the inhibition of CPT1. Therefore, UA can attenuate cardiac mitochondrial dysfunction and reduce myocardial apoptosis by restoring the balance of mitochondrial fatty acid oxidation metabolism. CPT1 may be a potential target. This study has substantial implications for advancing our understanding of the pathogenesis and drug development of SACI.

Urolithin A’s Role in Alleviating Severe Acute Pancreatitis via Endoplasmic Reticulum-Mitochondrial Calcium Channel Modulation

“…For example, pomegranate has anti-inflammatory and antioxidant effects, and its main component EA, and its metabolite UA have shown great potential in treating AP. 17,33 Currently, plants can encapsulate their effective components by secreting EVs, so we observed the effects of P-EVs and UA on pancreatic acinar cells. Compared with P-EVs, UA can significantly inhibit the necrosis of pancreatic acinar cells, reduce inflammation, and improve mitochondrial function, although P-EVs also showed certain antinecrosis and antioxidant abilities of acinar cells.…”

“…Excluding the sham group, all mice underwent SAP model establishment via retrograde infusion of taurocholic acid sodium salt hydrate into their pancreatic duct as per the published protocol . Based on our established experience from previous studies, mice in the UA group were intraperitoneally injected with UA (30 mg/kg, dissolved in 0.1% dimethyl sulfoxide) 1 h before and 3 h after modeling. Mice in the Ru360 group were administered with Ru360 (0.01 μM/kg) by intraperitoneal injection 30 min before SAP induction.…”

“…16 In a previous study, our research group found that UA can reduce the heart damage of SAP mice by regulating the fatty acid metabolism of myocardial mitochondria. 17 At present, more and more literature reports that plantderived extracellular vesicles (EVs) encapsulate the medicinal substances of their homologous plants and play an important role in regulating disease development and physiological processes through the intercellular exchange of bioactive molecules, such as protein, nucleic acids, and lipids. 18 Their structure and morphology are similar to EV secreted by mammals, 19 and they have a lipid bilayer, 20 which may represent a novel therapeutic approach.…”

“…Under the action of intestinal microflora, EA can be effectively converted into Urolithin A (3,8-dihydroxyurolithin, UA), , which has captured our focus due to its pronounced anti-inflammatory properties . In a previous study, our research group found that UA can reduce the heart damage of SAP mice by regulating the fatty acid metabolism of myocardial mitochondria …”