Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.
<h4>Objective</h4>Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reve...
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oai:doaj.org-article:7274581cba064ece9f3cedad3694c8892021-11-18T07:40:58ZNiacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.1932-620310.1371/journal.pone.0066467https://doaj.org/article/7274581cba064ece9f3cedad3694c8892013-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0066467https://doaj.org/toc/1932-6203<h4>Objective</h4>Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).<h4>Approach and results</h4>Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2) = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2) = 0.20, P<0.001).<h4>Conclusion</h4>Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.Susan KühnastMieke C LouweMattijs M HeemskerkElsbet J PietermanJan B van KlinkenSjoerd A A van den BergJohannes W A SmitLouis M HavekesPatrick C N RensenJosé W A van der HoornHans M G PrincenJ Wouter JukemaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e66467 (2013) |
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Medicine R Science Q Susan Kühnast Mieke C Louwe Mattijs M Heemskerk Elsbet J Pieterman Jan B van Klinken Sjoerd A A van den Berg Johannes W A Smit Louis M Havekes Patrick C N Rensen José W A van der Hoorn Hans M G Princen J Wouter Jukema Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| description |
<h4>Objective</h4>Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).<h4>Approach and results</h4>Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2) = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2) = 0.20, P<0.001).<h4>Conclusion</h4>Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy. |
| format |
article |
| author |
Susan Kühnast Mieke C Louwe Mattijs M Heemskerk Elsbet J Pieterman Jan B van Klinken Sjoerd A A van den Berg Johannes W A Smit Louis M Havekes Patrick C N Rensen José W A van der Hoorn Hans M G Princen J Wouter Jukema |
| author_facet |
Susan Kühnast Mieke C Louwe Mattijs M Heemskerk Elsbet J Pieterman Jan B van Klinken Sjoerd A A van den Berg Johannes W A Smit Louis M Havekes Patrick C N Rensen José W A van der Hoorn Hans M G Princen J Wouter Jukema |
| author_sort |
Susan Kühnast |
| title |
Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| title_short |
Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| title_full |
Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| title_fullStr |
Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| title_full_unstemmed |
Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol. |
| title_sort |
niacin reduces atherosclerosis development in apoe*3leiden.cetp mice mainly by reducing nonhdl-cholesterol. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/7274581cba064ece9f3cedad3694c889 |
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