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6. Geranylgeranylacetone ameliorated ischemia/reperfusion induced-blood brain barrier breakdown through HSP70-dependent anti-apoptosis effect

Author

Li, Fazhao, Gong, Xiyu, and Yang, Binbin

Subjects
Original Article
Abstract

Background: Geranylgeranylacetone (GGA) has been recently reported to be centrally active after oral administration and protect against ischemic brain injury. This study was aimed to investigate the underlying mechanism of the protective effect of GGA. Methods: In this study, transient middle cerebral artery occlusion (tMCAO) was established. Neurological score and brain water content were adopted to investigate the role of GGA in vivo. Evans-blue (EB), western blot and immunofluorescence staining of tight junction proteins were performed to evaluate blood brain barrier (BBB) permeability. Inflammation response was assessed by immunofluorescence staining of MPO and Iba-1 and quantitative real-time polymerase chain reaction (qRT-PCR) of proinflammatory cytokines. In in vitro experiment, after oxygen-glucose deprivation (OGD), transepithelial electrical resistance (TEER) and endothelial cell monolayer permeability assay were conducted to examine the effects of GGA on barrier integrity. Furthermore, heat shock protein (HSP) 70 expression was knockdown by RNA interference in bEnd.3 cells to verify the involvement of HSP70 in the action of GGA. TEER, endothelial cell monolayer permeability, CCK8 and flow cytometry were performed. Expression of caspase-3 was detected by western blot and immunofluorescence staining. Results: Our results indicated that pretreatment with a single oral GGA dose (800 mg/kg) reduced the infarct volume and prevented the neurological impairments after tMCAO. Importantly, GGA ameliorated cerebral ischemia/reperfusion (I/R) induced BBB breakdown and rescued tight junction proteins (TJPs). GGA also profoundly decreased neutrophil infiltration, inhibited glial activation and reduced the expression of proinflammatory cytokines. Consistently, GGA significantly decreased OGD-induced BBB hyper-permeability in vitro. Consistent with the previous studies, GGA promoted HSP70 induction after I/R insult. Mechanistic study showed that GGA inhibited OGD-induced apoptosis of bEnd.3 cells. Genetic inhibition of HSP70 attenuated GGA’s anti-apoptotic effect and reversed the protective effects of GGA.

Published
2021

10. Fropofol prevents disease progression in mice with hypertrophic cardiomyopathy.

Author

Huang, Yiyuan, Lu, Haisong, Ren, Xianfeng, Li, Fazhao, Bu, Weiming, Liu, Wenjie, Dailey, William P, Saeki, Harumi, Gabrielson, Kathleen, Abraham, Roselle, Eckenhoff, Roderic, and Gao, Wei Dong

Subjects
HYPERTROPHIC cardiomyopathy, DISEASE progression, MOUSE diseases, CELL size, PATHOLOGY, INTRA-abdominal hypertension
Abstract

Aims  Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development. Methods and results  Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human α-myosin heavy chain R403Q mutation (αMHC 403/+). αMHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12 weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+]i in isolated muscles from both WT and αMHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+]i required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis. Conclusions  Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression. [ABSTRACT FROM AUTHOR]

Published
2020
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12. FROPOFOL PREVENTS DISEASE PROGRESSION IN HYPERTROPHIC CARDIOMYOPATHY

Author

Huang, Yiyuan, primary, Lu, Haisong, additional, Li, Fazhao, additional, Liu, Wenjie, additional, Ren, Xianfeng, additional, Bu, Weiming, additional, Woll, Kellie A., additional, Leinwand, Leslie A., additional, Abraham, Roselle, additional, Eckenhoff, Roderic, additional, and Gao, Wei Dong, additional

Published
2018
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