HMG-CoA reductase inhibitors: Atorvastatin and simvastatin. Hypocholesterolemic mechanisms of action in the guinea pig

Coronary heart disease (CHD) is the number one cause of mortality and morbidity in the United States. Elevated levels of plasma cholesterol are considered a risk factor for CHD. Thus, reducing plasma cholesterol is associated with decreases in CHD risk. HMG-CoA reductase inhibitors or statins are pharmacological agents that lower total plasma cholesterol.^ The purpose of these studies was to determine the specific mechanisms by which atorvastatin (AT) and simvastatin (Sim), two HMG-CoA reductase inhibitors, lower plasma cholesterol. Guinea pigs were used as the animal model because their lipoprotein profile and responses to drugs are similar to humans.^ Guinea pigs were fed hypercholesterolemic diets with different concentrations of AT or Sim. AT and Sim treatment resulted in a dose dependent reduction of plasma LDL cholesterol and apo B concentrations. AT treatment yielded cholesteryl ester depleted LDL, while simvastatin resulted in LDL with higher triacylglycerols. In addition, both drugs were equally effective in decreasing in vitro LDL susceptibility to oxidation and cholesteryl ester transfer protein activity suggesting an important effect of statins in the intravascular processing of lipoproteins.^ Compared to control animals, AT and Sim treated groups had higher number of hepatic apo B/E receptors and faster LDL fractional catabolic rate. In addition, AT treatment resulted in the secretion of less number of VLDL particles suggesting that AT not only accelerated LDL clearance, but also affected VLDL synthesis.^ Simvastatin treatment had no effect on hepatic HMG-CoA reductase mRNA abundance. However, after guinea pigs were fasted for 6-18 h, Sim caused an up-regulation of enzyme activity that might be related to activation of existing protein or protein stabilization once Sim was removed from the active site of the enzyme. In contrast, AT treatment resulted in an increase in HMG-CoA reductase mRNA and no effect on enzyme activity even after 18h of fasting, which suggests that AT continued bound to the enzyme.^ From these studies we conclude that although AT and Sim are equally efficacious in reducing plasma cholesterol, there are important differences between statins in the molecular and metabolic regulation of hepatic enzymes and lipoprotein metabolism.

Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture

Background: Atherosclerotic plaque ruptures, triggered by blood flow–associated biomechanical forces, cause most myocardial infarctions and strokes. Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. Results: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. Conclusions: Our findings show plaque site–specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.</p

Incretin-like effects of small molecule trace amine-associated receptor 1 agonists

Objective: Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight. Methods: We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice. Results: TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls. Conclusions: We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity

Discovery of 2‑[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β Agonist in Clinical Trials for the Treatment of Dyslipidemia

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (<b>53</b>), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound <b>53</b> showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, <b>53</b> exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks