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.

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.

Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations.

BACKGROUND: Atherosclerosis is thought to be a disease of modern human beings and related to contemporary lifestyles. However, its prevalence before the modern era is unknown. We aimed to evaluate preindustrial populations for atherosclerosis. METHODS: We obtained whole body CT scans of 137 mummies from four different geographical regions or populations spanning more than 4000 years. Individuals from ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America, and the Unangan of the Aleutian Islands were imaged. Atherosclerosis was regarded as definite if a calcified plaque was seen in the wall of an artery and probable if calcifications were seen along the expected course of an artery. FINDINGS: Probable or definite atherosclerosis was noted in 47 (34%) of 137 mummies and in all four geographical populations: 29 (38%) of 76 ancient Egyptians, 13 (25%) of 51 ancient Peruvians, two (40%) of five Ancestral Puebloans, and three (60%) of five Unangan hunter gatherers (p=NS). Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Age at time of death was positively correlated with atherosclerosis (mean age at death was 43 [SD 10] years for mummies with atherosclerosis vs 32 [15] years for those without; p<0·0001) and with the number of arterial beds involved (mean age was 32 [SD 15] years for mummies with no atherosclerosis, 42 [10] years for those with atherosclerosis in one or two beds, and 44 [8] years for those with atherosclerosis in three to five beds; p<0·0001). INTERPRETATION: Atherosclerosis was common in four preindustrial populations including preagricultural hunter-gatherers. Although commonly assumed to be a modern disease, the presence of atherosclerosis in premodern human beings raises the possibility of a more basic predisposition to the disease. FUNDING: National Endowment for the Humanities, Paleocardiology Foundation, The National Bank of Egypt, Siemens, and St Luke's Hospital Foundation of Kansas City.

Atherosclerosis in mummified human remains from Vilnius, Lithuania (18th-19th centuries AD): a computed tomographic investigation.

OBJECTIVE: Through the study of preserved human remains, it is now known that atherosclerosis, commonly thought to be a modern disease, also existed in historic and prehistoric periods. To date, however, little evidence of atherosclerosis has been reported in samples of tissues from spontaneously mummified bodies that are often found in European crypts and churches. METHODS: Within the framework of the Lithuanian Mummy Project, whole-body computed tomographic scans of seven spontaneous mummies from a crypt in Vilnius were obtained and assessed for indications of atherosclerosis. RESULTS: Three of the mummies investigated showed clear evidence of atherosclerosis, which was at times quite severe. Atherosclerosis is believed to have been prevalent among affluent members of Lithuanian society, which is corroborated by historical sources. CONCLUSIONS: In accordance with recent, significant data, this study further demonstrates the antiquity of this disease. Documentary and ethnographic data suggest that lifestyle may have played a role in the onset of atherosclerosis in these individuals.

In celebration of the 100th anniversary of the lipid hypothesis of atherosclerosis.

This year marks the 100th anniversary of the publication of Anitschkow's classic paper proposing the central role of hypercholesterolemia in atherogenesis. We at the Journal of Lipid Research take this occasion to acknowledge the debt we all owe to Anitschkow and his colleagues for getting us on the right track. As discussed below in detail, his contributions were insightful and went well beyond simply pinpointing hypercholesterolemia as a major etiologic factor. Anitschkow's work led him to define most of the key elements in the initiation and evolution of lesions in animal models of atherogenesis.

Plaque attack: one hundred years of atherosclerosis in The American Journal of Pathology.

Research articles on atherosclerosis have been well represented in The American Journal of Pathology (AJP), with more than 500 articles published since 1925. An initial focus on descriptive studies led to the proposal that atherosclerosis occurs as a response to vascular injury. With time, this view was modified by a greater understanding of the roles played by lipids and integrity of the vessel wall's constituent cells and matrix. AJP has been a major contributor to the field, publishing numerous seminal research papers and review articles on the latest advances in atherosclerosis. This Centennial Review highlights these myriad contributions.

[Progress in researches on ancient history of atherosclerosis].

Atherosclerosis has been thought to be a disease of modern society, and its occurrence was closely related to contemporary diet and lifestyle. However, a series of investigations on ancient mummies by autopsy and CT scan concluded that atherosclerosis was commonly seen in ancient times. The presence of atherosclerosis in ancient human beings suggested that aging and genetic predisposition might be essential risk factors for atherosclerosis.

Diet and chronic diseases: INCAP studies of atherosclerosis and coronary heart disease.

This paper describes early INCAP studies showing that cholesterol and lipoprotein levels were much lower in the low-income populations of Central America than values that were just beginning to emerge from industrialized countries. These led to the collection of aortas and coronary vessels from 14,610 males and 7,906 females from serial autopsies from 12 public general hospitals in developing countries, mostly in Latin America and in New Orleans and Oslo. The severity of atherosclerotic lesions in the samples was evaluated independently by four pathologists after the samples were randomized, who determined that the severity of atherosclerosis progressed so slowly in the developing country samples that it rarely became clinically significant. The strongest correlation with the severity of lesions was the fat content of the diet.

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.