Ursolic Acid Ameliorates Myocardial Ischaemia/Reperfusion Injury by Improving Mitochondrial Function via Immunoproteasome-PP2A-AMPK Signalling

Abstract

Cardiac ischaemia/reperfusion (I/R) injury causes cardiomyocyte apoptosis and mitochondrial dysfunction. Ursolic acid (UA), as a pentacyclic triterpenoid carboxylic acid, exerts several bioactivities in animal models of different diseases, but the preventive role of UA in I/R-induced myocardial dysfunction remains largely unknown. Male wild-type mice were pre-administered with UA at a dosage of 80 mg/kg i.p. and then subjected to cardiac I/R injury for 24 h. Cardiac function and pathological changes were examined by echocardiography and histological staining. The protein and mRNA levels of the genes were determined using qPCR and immunoblotting analysis. Our results revealed that UA administration in mice significantly attenuated the I/R-induced decline in cardiac function, infarct size, myocyte apoptosis, and oxidative stress. Mechanistically, UA increased three immunoproteasome catalytic subunit expressions and activities, which promoted ubiquitinated PP2A degradation and activated AMPK-PGC1α signalling, leading to improved mitochondrial biosynthesis and dynamic balance. In vitro experiments confirmed that UA treatment prevented hypoxia/reperfusion (H/R)-induced cardiomyocyte apoptosis and mitochondrial dysfunction through activation of AMPK signalling. In summary, our findings identify UA as a new activator of the immunoproteasome that exerts a protective role in I/R-induced myocardial dysfunction and suggest that UA supplementation could be beneficial for the prevention of cardiac ischaemic disease.

MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling

“…Although numerous proteasome inhibitors, such as bortezomib (velcade), have been developed and can be safely administered to treat blood tumours with few side effects, very few molecules have been identified as potentially effective proteasome enhancers to date. Recently, we identified that ursolic acid (UA) is a new enhancer of immunoproteasome subunit expression that can prevent cardiac I/R injury [ 14 ]. Furthermore, several signalling mediators, such as STAT and cAMP-response element-binding protein (CREB), can increase immunoproteasome subunit transcription [ 42 ].…”

“…A total of 20 μg lysate proteins were added to 50 μl of reaction buffer that contains three fluorogenic peptides, including Z -nLPnLD-Glo™ (40 μM), Z -LRR-Glo™ (30 μM), or Suc-LLVY-Glo™ (40 μM), and reacted at RT for 10 min. Proteasomal activities (caspase-like, trypsin-like, and chymotrypsin-like) in the tissues were evaluated using Proteasome-Glo assay kit following the manufacturer's instructions (Promega) as previously reported [ 14 ]. The fluorescence intensities were measured with an automatic microplate reader (Spark).…”

Protein phosphatase 2A modulation and connection with miRNAs and natural products

“…36 Wongam, a licoricederived natural product, suppresses IL-1beta-promoted chondrocyte hypertrophy and nuclear translocation of histone deacetylase 4 (HDCA4), downregulated by PP2A inhibitor okadaic acid. 37 This result suggests that wongam upregulates PP2A ( Granulocyte-macrophage Nodularin 49 Liver cells Ursolic acid 50 Heart Chaetomellic anhydride 51 7-Deoxy-okadaic acid 52 Dinophysistoxin-4 53 Hipposulfate C 54 Halisulfate-7 54 Irregularasulfate 54…”

“…48 Ursolic acid upregulates catalytic caspase-, trypsin-, and chymotrypsin-like proteasomes of heart tissues to reduce myocardial ischemia/reperfusion injury, enhancing ubiquitinated PP2A degradation and mitochondrial biosynthesis. 50 Dinophysistoxin-4, 53 nonadrides, and chaetomellic anhydride 51 exhibit PP2A-inhibitory effects. An okadaic acid-derived synthetic marine natural product, 7-deoxy-okadaic acid, is a potential PP2A inhibitor.…”

“…[12][13][14] The discovery of drugs that modulate PP2A may regulate several diseases and cancer developments. 11 Many natural products show PP2A-modulating functions (activating and inhibitory [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] ), but lack comprehensive organization (Figure 2), particularly for microRNA (miRNA) modulation and their targeting investigation. miRNAs are F I G U R E 1 PP2A structure and its components.…”