Addition of the PCSK9 inhibitor, evolocumab, to statin therapy promoted coronary plaque stabilization after an acute coronary syndrome. While apolipoprotein B (ApoB) has been proposed as a goal for li Show more
Addition of the PCSK9 inhibitor, evolocumab, to statin therapy promoted coronary plaque stabilization after an acute coronary syndrome. While apolipoprotein B (ApoB) has been proposed as a goal for lipid-lowering therapy in the prevention of cardiovascular disease, its association with plaque stability has not been studied. The High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) used serial optical coherence tomography to assess coronary plaque phenotypes in patients with non-ST elevation myocardial infarction treated with evolocumab plus statin or placebo plus statin for 52 weeks. Changes in plaque composition were studied in patients according to achievement of a goal ApoB level <65 mg/dL. Of 112 patients, 67 (59.8 %) achieved the ApoB goal and had lower ApoB values at follow-up compared with those not at goal (37.1 ± 15.0 vs 92.7 ± 19.4 mg/dL, P < 0.001). Patients achieving the ApoB goal demonstrated a greater increase in minimum fibrous cap thickness (+44.6 ± 36.0 vs +24.9 ± 38.1 μm, P = 0.007) and a more pronounced decrease in lipid arc (-57.8 ± 52.8 vs -27.0 ± 59.2°, P = 0.005) at follow-up, compared with those who did not achieve the ApoB goal. At follow-up, thin-cap fibroatheroma (TCFA) was less prevalent among patients achieving the ApoB goal compared with those not at goal (9.0 vs. 40.0 %, P < 0.001). Multivariate analysis demonstrated that achieving an ApoB <65 mg/dL at follow-up independently associated with the absence of TCFA at follow-up (P = 0.004). Lower achieved ApoB levels associated with evidence of greater plaque stabilization even after controlling for low-density lipoprotein cholesterol levels. This highlights the importance of optimizing ApoB levels for the reduction of cardiovascular risk. NCT03570697. Show less
The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular regulated kinase) and p38α/β MAPK pathways. Show more
The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular regulated kinase) and p38α/β MAPK pathways. The MNKs have previously been implicated in metabolic disease and shown to mediate diet-induced obesity. In particular, knockout of MNK2 in mice protects from the weight gain induced by a high-fat diet. These and other data suggest that MNK2 regulates the expansion of adipose tissue (AT), a stable, long-term energy reserve that plays an important role in regulating whole-body energy homeostasis. Using the well-established mouse 3T3-L1 in vitro model of adipogenesis, the role of the MNKs in adipocyte differentiation and lipid storage was investigated. Inhibition of MNK activity using specific inhibitors failed to impair adipogenesis or lipid accumulation, suggesting that MNK activity is not required for adipocyte differentiation and does not regulate lipid storage. However, small-interfering RNA (siRNA) knock-down of MNK2 did reduce lipid accumulation and regulated the levels of two major lipogenic transcriptional regulators, ChREBP (carbohydrate response element-binding protein) and LPIN1 (Lipin-1). These factors are responsible for controlling the expression of genes for proteins involved in de novo lipogenesis and triglyceride synthesis. The knock-down of MNK2 also increased the expression of hormone-sensitive lipase which catalyses the breakdown of triglyceride. These findings identify MNK2 as a regulator of adipocyte metabolism, independently of its catalytic activity, and reveal some of the mechanisms by which MNK2 drives AT expansion. The development of an MNK2-targeted therapy may, therefore, be a useful intervention for reducing weight caused by excessive nutrient intake. Show less