File Download
Supplementary
-
Citations:
- Appears in Collections:
postgraduate thesis: The role of fatty acid-binding protein 4 in ischemic stroke
Title | The role of fatty acid-binding protein 4 in ischemic stroke |
---|---|
Authors | |
Advisors | Advisor(s):Cheung, RTF |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Ma, K. [马可]. (2023). The role of fatty acid-binding protein 4 in ischemic stroke. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Ischemic stroke (IS) ranks the second leading cause of mortality and a primary cause of long term disability in adults. Recanalization is the only proven medical therapy for IS patients in the acute phase. In addition to its limited application due to short therapeutic time window and potentially serious adverse effects, recanalization induces inflammation mediated reperfusion injury. Thus, it is important to find novel therapeutic targets to enhance neuronal survival either before or after recanalization, focusing specifically on modulating IS induced inflammation.
Fatty acid binding protein 4 (FABP4) is an abundant adipokine. As an inhibitor, BMS309403 has been shown promising in treating various cardiac and metabolic diseases. Clinical studies have shown a positive correlation between circulating FABP4 levels and ischemia severity. Experimental studies have revealed the detrimental effects of elevated FABP4 levels in the disruption of the blood--brain barrier (BBB). However, the functional roles of FABP4 in IS pathogenesis remain unclear.
In in vivo study, transient middle cerebral artery occlusion (MCAO) was applied to both non obese and obese mice to mimic IS in patients. Diet induced obesity (DIO) exacerbated ischemic damage and increased cerebral FABP4 levels. In both non obese and obese MCAO mice, cerebral FABP4 levels were upregulated with two peaks following ischemia. The expression of FABP4 was first observed in infiltrated monocytes and then in macrophages. In both non-obese and obese MCAO mice, BMS309403 treatment attenuated ischemic injury with improved neurological functions and reduced infarct volume.
In vitro oxygen glucose deprivation/reoxygenation (OGD/R) experiments were conducted. Differentiated human neuroblastoma SH SY5Y cells were subjected to OGD/R injury, and the culture medium was then harvested and prepared as the conditional medium (CM). A 24 hour incubation in the CM increased the FABP4 expression in human monocyte THP 1 cells. To determine the effects of BMS309403 on neuronal survival after OGD/R injury, a co culture system involving SH SY5Y and THP 1 cells was established. OGD/R induced loss of differentiated SH SY5Y cells was reduced in the co culture system with BMS309403 treated THP 1 cells.
To gain mechanistic insights, the effects of BMS309403 on post stroke inflammation were assessed using both in vivo and in vitro IS models. In both non obese and obese MCAO mice, BMS309403 inhibited the nuclear factor kappa B (NF‑κB) and peroxisome proliferator activated receptor gamma pathways and decreased the levels of interleukin (IL)--1β, tumor necrosis factor--α, and inducible nitric oxide synthase. In CM--treated THP--1 cells, BMS309403 reduced the expression of IL--1β via downregulating the NF‑κB pathway.
In conclusion, the putative neuroprotective role of BMS309403 is seen in both non obese and obese MCAO mice as well as OGD/R treated differentiated SH SY5Y cells. Its beneficial effects are partly mediated via regulating monocyte mediated inflammation through the NF‑κB pathway. FABP4 inhibition may be a promising novel therapeutic target in IS.
|
Degree | Doctor of Philosophy |
Subject | Fatty acid-binding proteins Cerebrovascular disease |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/335918 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Cheung, RTF | - |
dc.contributor.author | Ma, Ke | - |
dc.contributor.author | 马可 | - |
dc.date.accessioned | 2023-12-29T04:04:50Z | - |
dc.date.available | 2023-12-29T04:04:50Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Ma, K. [马可]. (2023). The role of fatty acid-binding protein 4 in ischemic stroke. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/335918 | - |
dc.description.abstract | Ischemic stroke (IS) ranks the second leading cause of mortality and a primary cause of long term disability in adults. Recanalization is the only proven medical therapy for IS patients in the acute phase. In addition to its limited application due to short therapeutic time window and potentially serious adverse effects, recanalization induces inflammation mediated reperfusion injury. Thus, it is important to find novel therapeutic targets to enhance neuronal survival either before or after recanalization, focusing specifically on modulating IS induced inflammation. Fatty acid binding protein 4 (FABP4) is an abundant adipokine. As an inhibitor, BMS309403 has been shown promising in treating various cardiac and metabolic diseases. Clinical studies have shown a positive correlation between circulating FABP4 levels and ischemia severity. Experimental studies have revealed the detrimental effects of elevated FABP4 levels in the disruption of the blood--brain barrier (BBB). However, the functional roles of FABP4 in IS pathogenesis remain unclear. In in vivo study, transient middle cerebral artery occlusion (MCAO) was applied to both non obese and obese mice to mimic IS in patients. Diet induced obesity (DIO) exacerbated ischemic damage and increased cerebral FABP4 levels. In both non obese and obese MCAO mice, cerebral FABP4 levels were upregulated with two peaks following ischemia. The expression of FABP4 was first observed in infiltrated monocytes and then in macrophages. In both non-obese and obese MCAO mice, BMS309403 treatment attenuated ischemic injury with improved neurological functions and reduced infarct volume. In vitro oxygen glucose deprivation/reoxygenation (OGD/R) experiments were conducted. Differentiated human neuroblastoma SH SY5Y cells were subjected to OGD/R injury, and the culture medium was then harvested and prepared as the conditional medium (CM). A 24 hour incubation in the CM increased the FABP4 expression in human monocyte THP 1 cells. To determine the effects of BMS309403 on neuronal survival after OGD/R injury, a co culture system involving SH SY5Y and THP 1 cells was established. OGD/R induced loss of differentiated SH SY5Y cells was reduced in the co culture system with BMS309403 treated THP 1 cells. To gain mechanistic insights, the effects of BMS309403 on post stroke inflammation were assessed using both in vivo and in vitro IS models. In both non obese and obese MCAO mice, BMS309403 inhibited the nuclear factor kappa B (NF‑κB) and peroxisome proliferator activated receptor gamma pathways and decreased the levels of interleukin (IL)--1β, tumor necrosis factor--α, and inducible nitric oxide synthase. In CM--treated THP--1 cells, BMS309403 reduced the expression of IL--1β via downregulating the NF‑κB pathway. In conclusion, the putative neuroprotective role of BMS309403 is seen in both non obese and obese MCAO mice as well as OGD/R treated differentiated SH SY5Y cells. Its beneficial effects are partly mediated via regulating monocyte mediated inflammation through the NF‑κB pathway. FABP4 inhibition may be a promising novel therapeutic target in IS. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Fatty acid-binding proteins | - |
dc.subject.lcsh | Cerebrovascular disease | - |
dc.title | The role of fatty acid-binding protein 4 in ischemic stroke | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2023 | - |
dc.identifier.mmsid | 991044657076503414 | - |