| 1 | SGLT2 inhibitor empagliflozin alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease显示文摘Recent evidence shows a close link between Parkinson's disease(PD)and cardiac dysfunction with limited treatment options.Mitophagy plays a crucial role in the control of mitochondrial quantity,metabolic reprogramming and cell differentiation.Mutation of the mitophagy protein Parkin is directly associated with the onset of PD.Parkin-independent receptor-mediated mitophagy is also documented such as BCL2/adenovirus E1B 19 kDa protein-interacting protein 3(BNIP3)and FUN14 domain containing 1(FUNDC1)for receptor-mediated mitophagy.In this study we investigated cardiac function and mitophagy including FUNDC1 in PD patients and mouse models,and evaluated the therapeutic potential of a SGLT2 inhibitor empagliflozin.MPTP-induced PD model Was established.PD patients and MPTP mice not only displayed pronounced motor defects,but also low plasma FUNDC1 levels,as well as cardiac ultrastructural and geometric anomalies(cardiac atrophy,interstitial fibrosis),functional anomalies(reduced E/A ratio,fractional shortening,ejection fraction,cardiomyocyte contraction)and mitochondrial injury(ultrastructural damage,UcP2,PGC1a,elevated mitochondrial Ca2+uptake proteins MCU and VDAC1,and mitochondrial apoptotic protein calpain),dampened autophagy,FUNDC1 mitophagy and apoptosis.By Gene set enrichment analysis(GSEA),we found overtly altered glucose transmembrane transport in the midbrains of MPTP-treated mice.Intriguingly,administration of SGLT2 inhibitor empagliflozin(10 mg/kg,ip,twice per week for 2 weeks)in MPTP-treated mice significantly ameliorated myocardial anomalies(with exception of VDAC1),but did not reconcile the motor defects or plasma FUNDCi.FUNDC1 global knockout(FUNDC1-/-mice)did not elicit any phenotype on cardiac geometry or function in the absence or presence of MPTP insult,but it nullified empagliflozin-caused cardioprotection against MPTP-induced cardiac anomalies including remodeling(atrophy and fibrosis),contractile dysfunction,Ca2+homeostasis,mitochondrial(including MCU,mitochondrial Ca2+overload,calpain,PARP1)and apoptotic anomalies.In neonatal and adult cardiomyocytes,treatment with PD neurotoxin preformed fibrils of a-synuclein(PFF)caused cytochrome c release and cardiomyocyte mechanical defects.These effects were mitigated by empagliflozin(10μM)or MCU inhibitor Ru360(10μM).MCU activator kaempferol(10μM)or calpain activator dibucaine(500μM)nullified the empagliflozin-induced beneficial effects.These results suggest that empagliflozin protects against PD-induced cardiac anomalies,likely through FUNDC1-mediated regulation of mitochondrial integrity. | Wei Yu Lin Wang Wei-ying Ren Hai-xia Xu Ne N.Wu Dong-hui Yu Russel J.Reiter Wen-liang Zha Qing-dong Guo Jun Ren | 2024 | Acta Pharmacologica Sinica2024，45，1： | 0 |
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