Atherosclerosis: Known and unknown

Abstract

Atherosclerotic disease, such as myocardial infarction and stroke, is the number one killer worldwide. Atherosclerosis is considered to be caused by multiple factors, including genetic and environmental factors. In humans, it takes several decades until the clinical complications develop. There are many known risk factors for atherosclerosis, including hypercholesterolemia, hypertension, diabetes and smoking, which are involved in the pathogenesis of atherosclerosis; however, it is generally believed that atherosclerosis is vascular chronic inflammation initiated by interactions of these risk factors and arterial wall cells. In the past 30 years, the molecular mechanisms underlying the pathogenesis of atherosclerosis have been investigated extensively using genetically modified animals, and lipid-reducing drugs, such as statins, have been demonstrated as the most effective for the prevention and treatment of atherosclerosis. However, despite this progress, questions regarding the pathogenesis of atherosclerosis remain and there is a need to develop new animal models and novel therapeutics to treat patients who cannot be effectively treated by statins. In this review, we will focus on two topics of atherosclerosis, "pathology" and "pathogenesis," and discuss unanswered questions.

Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis

“…Hypercholesterolemia represents another risk factor in the development of cardiovascular disease. Increased cholesterol, LDL levels and LDL/HDL ratio are associated with a sedentary lifestyle and western diets, which lead to endothelial dysfunction and progression of the atherosclerotic lesion [ 33 ]. DM is another significant contributor to atherosclerosis development.…”

Disfunção endotelial e Aterosclerose

“…A Angiotensina II (Ang II) atua diretamente em seu receptor do tipo I (AT1), promovendo a contração da musculatura lisa, produção de EROs e sequestrando o NO (SUZUKI et al, 2003;TODA et al, 2007), a expressão de interleucina-6 (IL-6) e da proteína quimiotática de monócitos (MCP-1), além de hiper-regular a molécula de adesão de célula vascular (VCAM-1), promovendo a inflamação do endotélio, condições essenciais para o desenvolvimento da aterosclerose. A partir da influência de diversos fatores de risco, há o estímulo de maior produção de Ang II e aldosterona, que favorece o aumento do estresse oxidativo e do processo inflamatório do tecido vascular (FALK, 2006;SENCHENKOVA et al, 2010;FAN & WATANABE, 2022).…”

“…Além de citocinas inflamatórias, a interação CD40/CD40L aumenta também a atividade de metaloproteinases de matriz (MMP) nas células musculares lisas vasculares e macrófagos, responsáveis pela degradação do colágeno, sendo elas: MMP-1 (colagenase intersticial tipo 1), MMP-2 (gelatinase), MMP-3 (estromelisina 1) e MMP-9 (gelatinase B) (SOUZA & LAURINDO, 2002). Níveis elevados destas proteínas indicam risco aumentado de DCV, pois induzem a formação de placas com maior concentração lipídica e menor concentração de colágeno, consistindo em placas vulneráveis e suscetíveis a ruptura e, consequentemente, levando a isquemia tecidual (FALK, 2006;FAN & WATANABE, 2022;SOUZA, 2007).…”

“…A hipertensão é um importante fator de risco, visto que o progressivo e constante aumento dos níveis pressóricos estimulam a lesão endotelial, interferindo na permeabilidade vascular a fluidos e macromoléculas, favorecendo a formação da placa ateromatosa (PEREIRA et al, 2019). Esse aumento da pressão também pode ser provocado pela hiperinsulinemia,q eu juntamente com a elevação dos níveis lipídicos, propiciam o desenvolvimento da aterosclerose (CARVALHO, 2010;FALK, 2006;FAN & WATANABE, 2022). Além disso, a hiperglicemia, e hiperinsulinemia e a resistência insulínica em tempo prolongado acarretam diversas alterações celulares em todo o processo que compreende a aterosclerose, sendo a principal delas a diminuição da biodisponibilidade do óxido nítrico endovascular (WILSON & KANEL, 2002;AZEVEDO et al, 2010;BERTOLUCI, 2008;PICHÉ et al, 2020;NG et al, 2021).…”

Qihuang Zhuyu Formula Attenuates Atherosclerosis via Targeting PPARγ to Regulate Cholesterol Efflux and Endothelial Cell Inflammation

“…Atherosclerotic cardiovascular disease is one of the leading causes of death and disability worldwide today [ 2 ]. The occurrence and development of atherosclerosis involve many kinds of pathogenesis, such as endothelial injury, hemodynamic changes, inflammatory infiltration, smooth muscle cell proliferation, and abnormal cholesterol metabolism [ 3 ]. At present, the pharmacological mechanism of the three main drugs for the treatment of atherosclerosis, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, Niemann-pick C1-like protein 1 (NPC1L1) inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, is mainly to reduce cholesterol through affecting the synthesis, absorption, and degradation of cholesterol, respectively.…”