Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease

Jamie Morton, Shisan Bao, Laura Z. Vanags, Tania Tsatralis, Anisyah Ridiandries, Chung Wah Siu, Kwong Man Ng, Joanne Tan, David Celermajer, Martin K C Ng, Christina Bursill

Research output: Contribution to conferenceAbstract

Abstract

Introduction: Pre-clinical studies show high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are atheroprotective in early-stage disease, however, HDL-raising has not yet translated successfully for humans with established plaques.Aim: To determine the efficacy of apoA-I raising on late-stage vs. early-stage lesions and assess changes in key mechanisms of HDL functionality.Methods and Results: In a late-stage plaque model, apoE-/- mice first received high-fat diet (HFD) for 18-weeks before apoA-I was raised for 16 weeks via alternate day apoA-I infusions or lentiviral gene-transfer. In an early-stage model, apoE-/- mice first received HFD for 2 weeks before receiving alternate day apoA-I infusions for 6 weeks. We found apoA-I infusions into mice with late-stage lesions modestly decreased aortic sinus plaque area (8%, p<0.05) and had no effect on thoracic aorta lesions or plaque composition at each site. There were also no changes in adventitial neovascularization, as measured using MicroCT. Constitutive overexpression of apoA-I for 16 weeks by lentivirus also failed to change plaque area or composition in mice with late-stage disease. Conversely, apoA-I infusions in mice with early-stage disease had significantly reduced plaque area (30%), macrophage (51%) and extracellular-lipid content (23%), and increased smooth muscle cell content (34%), p≤0.01. ApoA-I reduced systemic inflammatory markers MCP-1 and SAA in early-stage but not late-stage disease. Ex vivo, HDL from apoA-I-infused mice with late-stage plaque had impaired functionality compared to HDL from apoA-I mice with early-stage disease. HDL from apoA-I mice with late-stage disease was less anti-inflammatory, as measured by VCAM-1 expression, and less anti-apoptotic, as measured by annexinV, via failure to induce anti-apoptotic protein Bcl-xL in human coronary artery endothelial cells. HDL from apoA-I mice with late-stage disease also had attenuated cholesterol efflux capacity in J774A.1 macrophages.Conclusions: In contrast to its beneficial effects in early-stage disease, apoA-I-raising in late-stage disease was associated with a striking attenuation of benefit. This suggests that in advanced atherosclerosis, the protective actions of HDL are compromised.
LanguageEnglish
Publication statusPublished - 14 Nov 2017
EventAHA Scientific Sessions 2017 - Anaheim, United States
Duration: 11 Nov 201715 Nov 2017

Conference

ConferenceAHA Scientific Sessions 2017
CountryUnited States
CityAnaheim
Period11/11/1715/11/17

Cite this

Morton, Jamie ; Bao, Shisan ; Vanags, Laura Z. ; Tsatralis, Tania ; Ridiandries, Anisyah ; Siu, Chung Wah ; Ng, Kwong Man ; Tan, Joanne ; Celermajer, David ; Ng, Martin K C ; Bursill, Christina. / Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease. Abstract from AHA Scientific Sessions 2017, Anaheim, United States.
@conference{8c7c820c68a042d2a8a2b063fdd2d945,
title = "Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease",
abstract = "Introduction: Pre-clinical studies show high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are atheroprotective in early-stage disease, however, HDL-raising has not yet translated successfully for humans with established plaques.Aim: To determine the efficacy of apoA-I raising on late-stage vs. early-stage lesions and assess changes in key mechanisms of HDL functionality.Methods and Results: In a late-stage plaque model, apoE-/- mice first received high-fat diet (HFD) for 18-weeks before apoA-I was raised for 16 weeks via alternate day apoA-I infusions or lentiviral gene-transfer. In an early-stage model, apoE-/- mice first received HFD for 2 weeks before receiving alternate day apoA-I infusions for 6 weeks. We found apoA-I infusions into mice with late-stage lesions modestly decreased aortic sinus plaque area (8{\%}, p<0.05) and had no effect on thoracic aorta lesions or plaque composition at each site. There were also no changes in adventitial neovascularization, as measured using MicroCT. Constitutive overexpression of apoA-I for 16 weeks by lentivirus also failed to change plaque area or composition in mice with late-stage disease. Conversely, apoA-I infusions in mice with early-stage disease had significantly reduced plaque area (30{\%}), macrophage (51{\%}) and extracellular-lipid content (23{\%}), and increased smooth muscle cell content (34{\%}), p≤0.01. ApoA-I reduced systemic inflammatory markers MCP-1 and SAA in early-stage but not late-stage disease. Ex vivo, HDL from apoA-I-infused mice with late-stage plaque had impaired functionality compared to HDL from apoA-I mice with early-stage disease. HDL from apoA-I mice with late-stage disease was less anti-inflammatory, as measured by VCAM-1 expression, and less anti-apoptotic, as measured by annexinV, via failure to induce anti-apoptotic protein Bcl-xL in human coronary artery endothelial cells. HDL from apoA-I mice with late-stage disease also had attenuated cholesterol efflux capacity in J774A.1 macrophages.Conclusions: In contrast to its beneficial effects in early-stage disease, apoA-I-raising in late-stage disease was associated with a striking attenuation of benefit. This suggests that in advanced atherosclerosis, the protective actions of HDL are compromised.",
author = "Jamie Morton and Shisan Bao and Vanags, {Laura Z.} and Tania Tsatralis and Anisyah Ridiandries and Siu, {Chung Wah} and Ng, {Kwong Man} and Joanne Tan and David Celermajer and Ng, {Martin K C} and Christina Bursill",
year = "2017",
month = "11",
day = "14",
language = "English",
note = "AHA Scientific Sessions 2017 ; Conference date: 11-11-2017 Through 15-11-2017",

}

Morton, J, Bao, S, Vanags, LZ, Tsatralis, T, Ridiandries, A, Siu, CW, Ng, KM, Tan, J, Celermajer, D, Ng, MKC & Bursill, C 2017, 'Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease' AHA Scientific Sessions 2017, Anaheim, United States, 11/11/17 - 15/11/17, .

Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease. / Morton, Jamie; Bao, Shisan; Vanags, Laura Z.; Tsatralis, Tania; Ridiandries, Anisyah; Siu, Chung Wah; Ng, Kwong Man; Tan, Joanne; Celermajer, David; Ng, Martin K C; Bursill, Christina.

2017. Abstract from AHA Scientific Sessions 2017, Anaheim, United States.

Research output: Contribution to conferenceAbstract

TY - CONF

T1 - Abstract 15639: Stage-specific Effects of Apolipoprotein (apo)A-I Raising in Atherosclerosis: ApoA-I Suppresses Plaque Size and Preserves High-density Lipoprotein Function in Apo E-/- Mice With Early Stage But Not Late-stage Disease

AU - Morton, Jamie

AU - Bao, Shisan

AU - Vanags, Laura Z.

AU - Tsatralis, Tania

AU - Ridiandries, Anisyah

AU - Siu, Chung Wah

AU - Ng, Kwong Man

AU - Tan, Joanne

AU - Celermajer, David

AU - Ng, Martin K C

AU - Bursill, Christina

PY - 2017/11/14

Y1 - 2017/11/14

N2 - Introduction: Pre-clinical studies show high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are atheroprotective in early-stage disease, however, HDL-raising has not yet translated successfully for humans with established plaques.Aim: To determine the efficacy of apoA-I raising on late-stage vs. early-stage lesions and assess changes in key mechanisms of HDL functionality.Methods and Results: In a late-stage plaque model, apoE-/- mice first received high-fat diet (HFD) for 18-weeks before apoA-I was raised for 16 weeks via alternate day apoA-I infusions or lentiviral gene-transfer. In an early-stage model, apoE-/- mice first received HFD for 2 weeks before receiving alternate day apoA-I infusions for 6 weeks. We found apoA-I infusions into mice with late-stage lesions modestly decreased aortic sinus plaque area (8%, p<0.05) and had no effect on thoracic aorta lesions or plaque composition at each site. There were also no changes in adventitial neovascularization, as measured using MicroCT. Constitutive overexpression of apoA-I for 16 weeks by lentivirus also failed to change plaque area or composition in mice with late-stage disease. Conversely, apoA-I infusions in mice with early-stage disease had significantly reduced plaque area (30%), macrophage (51%) and extracellular-lipid content (23%), and increased smooth muscle cell content (34%), p≤0.01. ApoA-I reduced systemic inflammatory markers MCP-1 and SAA in early-stage but not late-stage disease. Ex vivo, HDL from apoA-I-infused mice with late-stage plaque had impaired functionality compared to HDL from apoA-I mice with early-stage disease. HDL from apoA-I mice with late-stage disease was less anti-inflammatory, as measured by VCAM-1 expression, and less anti-apoptotic, as measured by annexinV, via failure to induce anti-apoptotic protein Bcl-xL in human coronary artery endothelial cells. HDL from apoA-I mice with late-stage disease also had attenuated cholesterol efflux capacity in J774A.1 macrophages.Conclusions: In contrast to its beneficial effects in early-stage disease, apoA-I-raising in late-stage disease was associated with a striking attenuation of benefit. This suggests that in advanced atherosclerosis, the protective actions of HDL are compromised.

AB - Introduction: Pre-clinical studies show high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are atheroprotective in early-stage disease, however, HDL-raising has not yet translated successfully for humans with established plaques.Aim: To determine the efficacy of apoA-I raising on late-stage vs. early-stage lesions and assess changes in key mechanisms of HDL functionality.Methods and Results: In a late-stage plaque model, apoE-/- mice first received high-fat diet (HFD) for 18-weeks before apoA-I was raised for 16 weeks via alternate day apoA-I infusions or lentiviral gene-transfer. In an early-stage model, apoE-/- mice first received HFD for 2 weeks before receiving alternate day apoA-I infusions for 6 weeks. We found apoA-I infusions into mice with late-stage lesions modestly decreased aortic sinus plaque area (8%, p<0.05) and had no effect on thoracic aorta lesions or plaque composition at each site. There were also no changes in adventitial neovascularization, as measured using MicroCT. Constitutive overexpression of apoA-I for 16 weeks by lentivirus also failed to change plaque area or composition in mice with late-stage disease. Conversely, apoA-I infusions in mice with early-stage disease had significantly reduced plaque area (30%), macrophage (51%) and extracellular-lipid content (23%), and increased smooth muscle cell content (34%), p≤0.01. ApoA-I reduced systemic inflammatory markers MCP-1 and SAA in early-stage but not late-stage disease. Ex vivo, HDL from apoA-I-infused mice with late-stage plaque had impaired functionality compared to HDL from apoA-I mice with early-stage disease. HDL from apoA-I mice with late-stage disease was less anti-inflammatory, as measured by VCAM-1 expression, and less anti-apoptotic, as measured by annexinV, via failure to induce anti-apoptotic protein Bcl-xL in human coronary artery endothelial cells. HDL from apoA-I mice with late-stage disease also had attenuated cholesterol efflux capacity in J774A.1 macrophages.Conclusions: In contrast to its beneficial effects in early-stage disease, apoA-I-raising in late-stage disease was associated with a striking attenuation of benefit. This suggests that in advanced atherosclerosis, the protective actions of HDL are compromised.

M3 - Abstract

ER -