A comprehensive account of insulin and LDL receptor activity over the years: A highlight on their signaling and functional role.

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.

Hitos históricos en el tratamiento hipolipemiante antes de la era de los inhibidores de la proproteina convertasa subtilisina/kexina tipo 9 / Historical milestones in lipid-lowering treatment before the era of proprotein convertase subtilisin/kexin type-9 inhibitors

Evidencia amplia y sólida respalda que el colesterol unido a lipoproteínas de baja densidad (LDL) es un factor causal de la ateroesclerosis. El uso de fármacos hipolipemiantes para reducir la carga aterogénica de las lipoproteínas que contienen la apoprotema B, principalmente las LDL, disminuye la tasa de progresion de la enfermedad ateromatosa e incluso puede revertirla si el tratamiento se inicia de manera precoz y agresiva. La presente revisión proporciona una perspectiva historica del desarrollo de los diferentes fármacos hipolipemiantes utilizados en la prevención cardiovascular, excluidos los inhibidores de la proproteina convertasa subtilisina/kexina 9, y resume los principales estudios clínicos prospectivos de intervención con cada uno de ellos para establecer los potenciales beneficios cardiovasculares en relación con su efecto reductor en las concentraciones de colesterol unido a LDL

There is extensive, strong evidence that low-density lipoprotein (LDL) cholesterol is a causal factor for atherosclerosis. The use of lipid-lowering drugs to reduce the atherogenic load of lipoproteins containing apolipoprotein B, mainly LDLs, slows the progression of atheromatous disease and could even reverse it if treatment is started early and aggressively. This review provides a historical perspective on the development of the various lipid-lowering drugs used for cardiovascular prevention, excluding proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, and summarizes the findings of the main prospective interventional clinical trials of individual agents in order to identify the potential cardiovascular benefits associated with their ability to reduce LDL-cholesterol concentrations

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease.

Animal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5) The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

High prevalence of cholesterol-rich atherosclerotic lesions in ancient mummies: A near-infrared spectroscopy study.

Computed tomography has been used previously in mummies to detect arterial calcification, which is a marker of later-stage atherosclerosis. Here, using the novel approach of near-infrared spectroscopy, we detected cholesterol-rich atherosclerotic plaques in arterial samples from ancient mummies. In this proof-of-concept study, we are the first to noninvasively detect these earlier-stage lesions in mummies from different geographical areas, suggesting that atherosclerosis has been present in humans since ancient times.

Non-genetic rats models for atherosclerosis research: from past to present.

Atherosclerosis is an inflammatory, progressive, and chronic illness that involves several molecular and epigenetic factors. Despite treatment limitations, clinical and therapeutic approaches have undeniably changed radically in recent decades through better knowledge of the pathophysiological basis of the disease, which has considerably improved patients' survival and quality of life. Some of these advances are attributable to basic biomedical research that provides insights into a better understanding and identification of new molecular and cellular targets for atherosclerosis treatment. Although rodent models have contributed substantially to a better understanding of the development of atherosclerosis, the accuracy of these models remains controversial. Research that utilizes genetic rodent models is well established, but the use of specific diets that are associated with other risk factors (e.g., hypertension, hormone deprivation, and pharmacological tools) is still debatable. The present review provides an update on non-genetic rat models of atherosclerosis and an overview of the main methodologies that are currently available.

Severe atherosclerosis in the natural mummy of Girolamo Macchi (1648-1734), "major writer" of Santa Maria della Scala Hospital in Siena (Italy).

BACKGROUND AND AIMS: A small crypt in the Santissima Annunziata Church of Santa Maria della Scala Hospital in Siena (Italy) contained three well-preserved mummies, two of which, dated back to the 15th-16th century, were identified as Salimbene Capacci (1433-1497), Rector of the Hospital, and his wife, Margherita Sozzini (?-1511). The third mummy, dressed in clothes of the 17th century, was not initially identified. METHODS: Accurate bibliographical, taphonomic and anthropological studies allowed the identification of the mummy of Girolamo Macchi, who lived between 1648 and 1734 and worked as "major writer", an accountant, for the Hospital. He was present when the corpses of the Rector and his wife were discovered in 1678 and, impressed by this finding, wanted to be buried in the same chapel after his death, which occurred at the age of 86. A complete study, including macroscopic, radiological, isotopic and histological analyses, was performed on the natural mummy of Girolamo. RESULTS: Macroscopic investigation showed a large inguinoscrotal hernia and a good preservation of the internal organs. The circulatory system revealed severe atherosclerosis, with multiple calcifications stenosing the lumen of the vessels, in particular of the lumbar aorta and the iliac arteries. The diagnosis was confirmed by imaging techniques (3D Cone Beam Scan) and by histology. CONCLUSIONS: This case confirms that atherosclerosis is also a disease of ancient times. The presence of atherosclerosis in pre-contemporary individuals could suggest that the disease may not only be uniquely characteristic of a specific diet or lifestyle, but it could be also an inherent component of human ageing.

History of lipidology and lipoprotein apheresis.

This review tells the story of atherosclerosis research in the beginning of the 20th century. It presents the significance of cardiovascular diseases and addresses major questions currently being discussed among lipidologists and the current thinking with respect to low LDL-cholesterol levels and HDL. It provides an overview of the period during which lipid-modifying drugs were introduced and their relevance with respect to cardiovascular outcome data and lists possible reasons why some patients develop new cardiovascular events while being treated with statins. Especially impressive is the history of the appearance of the PCSK9 inhibitors on the market - only 12 years after PCSK9 was detected; a study completed in 2017 provides evidence about the cardiovascular effects of these new drugs. Other new drugs are also mentioned: mipomersen, lomitapide, and Alipogen Tiparvovec. Some promising drugs are still in the pipeline which inhibit the synthesis of apolipoprotein CIII, apolipoprotein(a), and the PCSK9 protein. During the 1970s, specific lipoprotein apheresis began to be used in high-risk patients with homozygous familial hypercholesterolemia, severe hypercholesterolemia and elevated Lipoprotein(a) levels and this review provides evidence of the effectiveness of the extracorporeal therapy with respect to the reduction of cardiovascular events. Particularly in patients with high Lipoprotein(a) levels, apheresis has been proven capable of reducing cardiovascular events by more than 80%. The current situation with regard to lipoprotein apheresis centers and patients in Germany is described herein, and, in conclusion, an estimation of the future of the therapeutic options in lipidology is given.

Colesterol y aterosclerosis. Consideraciones históricas y tratamiento / Cholesterol and atherosclerosis. Historical considerations and treatment

Resumen El colesterol es un esteroide precursor de hormonas, componente esencial de la membrana celular, sin embargo, alteraciones en la regulación de la síntesis, absorción y excreción del colesterol predisponen al desarrollo de enfermedades cardiovasculares de origen aterosclerótico. De esta manera, reconociendo los acontecimientos históricos desde hace 200 años, con Michel Chevreul que le dio el nombre "colesterina", más tarde Lobstein que acuñó el término aterosclerosis y Marchand que lo introduce, Anichkov que identifica el colesterol en las placas de ateroma, y el descubrimiento del receptor LDL por Brown y Goldstein; además de la aparición de los diferentes fármacos que han surgido desde los fibratos, las estatinas y en esta década cetrapibs, muy prometedores para aumentar el HDL, en forma más reciente, ezetimibe y anti-PCSK9 para inhibir el proceso de degradación del receptor LDL; no obstante, estos avances no han sido suficientes para disminuir la morbilidad en enfermedades cardiovasculares.

Abstract Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming "cholesterol"; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease.