Phillip Gordts (United States of America)

University of California, San Diego Medicine

Author Of 1 Presentation

O029 - Interventional Hepatic ApoC-III Knockdown Improves Atherosclerotic Plaque Stability and Remodeling via Lowering Remnant Lipoproteins (ID 630)

Session Type
Lipoproteins and Metabolism
Session Time
16:00 - 17:30
Date
Mon, 31.05.2021
Room
Hall C
Lecture Time
16:41 - 16:49

Abstract

Background and Aims

Apolipoprotein C-III (apoC-III) is a key regulator in triglyceride metabolism and correlates positively with hypertriglyceridemia and incidences of CVD. Recent studies also identified apoC-III as an inducer of sterile inflammation by activating the inflammasome, another CVD risk factor. It remains unclear if therapeutic apoC-III lowering can reduce CVD risk, nor is it clear if this is depended on lipid-lowering or anti-inflammatory properties or both.

Methods

In this study, we determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotides (ASOs) in hypertriglyceridemic mouse models where the intervention results in triglyceride-lowering (Apoe-/-Ndst1f/fAlb-Cre+, Ldlr-/-Ndst1f/fAlb-Cre+) or not (Ldlr-/-Lrp1f/fAlb-Cre+).

Results

ApoC-III ASO treatment did not alter atherosclerotic lesion volume in the murine models mice simultaneously fed a Western diet. However, when triglyceride-lowering was obtained, apoC-III ASO treatment significantly attenuated advanced and unstable plaque development. In contrast, no improvement in lesion composition and hyperlipidemia was observed in apoC-III ASO-treated Ldlr-/-Lrp1f/fAlb-Cre+ mice. To mimic an intreventional setting we tested the impact of therapeutic apoC-III lowering in combination with a switch to a lipid-poor chow diet intervention after 12-week Western diet feeding. We observed that apoC-III ASO treatment significantly reduced atherosclerotic lesion size progression when an additive triglyceride-lowering was achieved. No differences in lesion development were observed in similarly treated Ldlr-/-Lrp1f/fAlb-Cre+ mice wherein no additive triglyceride-lowering was achieved by apoC-III ASO intervention.

Conclusions

Our data highlight that the impact of apoC-III on atherogenesis depends on its lipid-modifying properties. Hence, our findings suggest that interventional apoC-III lowering in hypertriglyceridemia patients can prevent plaques rupture and reduce CVD-associated mortality.

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Presenter of 1 Presentation

O029 - Interventional Hepatic ApoC-III Knockdown Improves Atherosclerotic Plaque Stability and Remodeling via Lowering Remnant Lipoproteins (ID 630)

Session Type
Lipoproteins and Metabolism
Session Time
16:00 - 17:30
Date
Mon, 31.05.2021
Room
Hall C
Lecture Time
16:41 - 16:49

Abstract

Background and Aims

Apolipoprotein C-III (apoC-III) is a key regulator in triglyceride metabolism and correlates positively with hypertriglyceridemia and incidences of CVD. Recent studies also identified apoC-III as an inducer of sterile inflammation by activating the inflammasome, another CVD risk factor. It remains unclear if therapeutic apoC-III lowering can reduce CVD risk, nor is it clear if this is depended on lipid-lowering or anti-inflammatory properties or both.

Methods

In this study, we determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotides (ASOs) in hypertriglyceridemic mouse models where the intervention results in triglyceride-lowering (Apoe-/-Ndst1f/fAlb-Cre+, Ldlr-/-Ndst1f/fAlb-Cre+) or not (Ldlr-/-Lrp1f/fAlb-Cre+).

Results

ApoC-III ASO treatment did not alter atherosclerotic lesion volume in the murine models mice simultaneously fed a Western diet. However, when triglyceride-lowering was obtained, apoC-III ASO treatment significantly attenuated advanced and unstable plaque development. In contrast, no improvement in lesion composition and hyperlipidemia was observed in apoC-III ASO-treated Ldlr-/-Lrp1f/fAlb-Cre+ mice. To mimic an intreventional setting we tested the impact of therapeutic apoC-III lowering in combination with a switch to a lipid-poor chow diet intervention after 12-week Western diet feeding. We observed that apoC-III ASO treatment significantly reduced atherosclerotic lesion size progression when an additive triglyceride-lowering was achieved. No differences in lesion development were observed in similarly treated Ldlr-/-Lrp1f/fAlb-Cre+ mice wherein no additive triglyceride-lowering was achieved by apoC-III ASO intervention.

Conclusions

Our data highlight that the impact of apoC-III on atherogenesis depends on its lipid-modifying properties. Hence, our findings suggest that interventional apoC-III lowering in hypertriglyceridemia patients can prevent plaques rupture and reduce CVD-associated mortality.

Hide