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Abstract: S3-17 ADRENAL SR-BI IS A NOVEL THERAPEUTIC TARGET IN STRESSINDUCED CARDIOVASCULAR DISEASE
- Post-meeting symposia - High Density Lipoproteins Abstract: S3-17 Citation: Atherosclerosis Supplement 2009, Vol. 10, Issue 2
ADRENAL SR-BI IS A NOVEL THERAPEUTIC TARGET IN STRESSINDUCED CARDIOVASCULAR DISEASE M Hoekstra, D Ye, R Hildebrand, T van Berkel, M van Eck LACDR, Leiden Objectives: Diminishing stress-induced adrenal steroidogenesis is considered to be a good therapeutic approach to battle cardiovascular diseases associated with stress. Scavenger receptor BI (SR-BI) is highly expressed in the adrenals and mediates the uptake of HDLcholesteryl esters (HDL-CE). In the current study, we determined the contribution of SR-BI to adrenal steroidogenesis in mice. Methods and Results: Impaired uptake of HDL-CE due to absence of SR-BI induced depletion of adrenal lipid stores and adrenal hypertrophy. Basal steroidogenesis was not affected by SRBI deficiency. In contrast, the LPS-induced plasma corticosterone level was significantly lower in SR-BI KO mice as compared to controls, which coincided with an increased susceptibility to inflammation. Transgenic expression of human cholesteryl ester transfer protein (CETP) in SRBI KO mice was able to normalize the rise in plasma cholesterol levels upon SR-BI deficiency due to its ability to transfer CE from HDL to ApoB-containing lipoproteins for uptake via the LDL receptor. However, CETP was unable to reverse the adrenal hypertrophy and lipid depletion in SR-BI knockout mice. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level upon a LPS challenge, leading to an identical >4-fold increased TNF-alpha response. These data indicate that uptake of cholesteryl esters via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. Conclusion: We have shown that in mice the uptake of HDL-CE by SR-BI is the rate-limiting step for stress-induced adrenal steroidogenesis. From our studies it is anticipated that adrenal SR-BI may be a novel therapeutic target for intervention in stress-induced CVD. Funding: Grants TIParma T2-110 and NHS 2007T056.
ADRENAL SR-BI IS A NOVEL THERAPEUTIC TARGET IN STRESSINDUCED CARDIOVASCULAR DISEASE M Hoekstra, D Ye, R Hildebrand, T van Berkel, M van Eck LACDR, Leiden Objectives: Diminishing stress-induced adrenal steroidogenesis is considered to be a good therapeutic approach to battle cardiovascular diseases associated with stress. Scavenger receptor BI (SR-BI) is highly expressed in the adrenals and mediates the uptake of HDLcholesteryl esters (HDL-CE). In the current study, we determined the contribution of SR-BI to adrenal steroidogenesis in mice. Methods and Results: Impaired uptake of HDL-CE due to absence of SR-BI induced depletion of adrenal lipid stores and adrenal hypertrophy. Basal steroidogenesis was not affected by SRBI deficiency. In contrast, the LPS-induced plasma corticosterone level was significantly lower in SR-BI KO mice as compared to controls, which coincided with an increased susceptibility to inflammation. Transgenic expression of human cholesteryl ester transfer protein (CETP) in SRBI KO mice was able to normalize the rise in plasma cholesterol levels upon SR-BI deficiency due to its ability to transfer CE from HDL to ApoB-containing lipoproteins for uptake via the LDL receptor. However, CETP was unable to reverse the adrenal hypertrophy and lipid depletion in SR-BI knockout mice. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level upon a LPS challenge, leading to an identical >4-fold increased TNF-alpha response. These data indicate that uptake of cholesteryl esters via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. Conclusion: We have shown that in mice the uptake of HDL-CE by SR-BI is the rate-limiting step for stress-induced adrenal steroidogenesis. From our studies it is anticipated that adrenal SR-BI may be a novel therapeutic target for intervention in stress-induced CVD. Funding: Grants TIParma T2-110 and NHS 2007T056.