## 3 Cardiovascular Diseases
### Atherosclerosis  
Atherosclerosis is a chronic, slow-progressing, immune-inflammatory, and fibroproliferative disease that begins with the activation of the endothelium, a process in which endothelial cells (ECs) begin to express adhesion molecules and pro-inflammatory cytokines, facilitating the adhesion and migration of leukocytes. A cascade of events follows, resulting in the narrowing of vessels and the activation of inflammatory pathways, ultimately resulting in the formation of atherosclerotic plaques. These plaques are characterised by the accumulation of lipids, fibrous elements, and calcification within the walls of medium and large arteries, which can lead to further cardiovascular complications [2; 108]. Hypertension, obesity, smoking, age, gender, family history, and dyslipidemia are some of the risk factors for atherosclerosis. Among these, dyslipidemia plays a particularly important role in the incidence and progression of atherosclerosis [109]. It is characterised by high plasma levels of cholesterol, triglycerides, or both, which are transported by lipoproteins. Based on their density and size, lipoproteins are classified into five categories: very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), intermediate-density lipoproteins (IDLs), high-density lipoproteins (HDLs), and chylomicrons. Each category has specific functions in the lipid metabolism, and together they contribute to maintaining a healthy vasculature [110]. In this context, LDLs are considered to be the most atherogenic lipoproteins, as they alter the properties of the endothelium, upregulate adhesion molecules, promote monocyte recruitment and differentiation into macrophages, and induce the proliferation of smooth muscle cells [2]. To provide a better understanding of the role of circulating lipoproteins in atherogenesis, Figure 4 summarises the main metabolic pathways of lipoproteins, including the exogenous, endogenous, and reverse cholesterol transport pathways. Figure 4: Overview of lipoprotein metabolism: exogenous pathway, endogenous pathway, and reverse cholesterol transport. This schematic illustrates the major pathways of the human lipoprotein metabolism, encompassing its synthesis, transformation, clearance, and the key proteins involved inlipid transport and regulation. **Blue arrows represent the exogenous pathway**, which begins with the absorption of dietary lipids in the small intestine and the assembly of chylomicrons, rich in triglycerides and apolipoprotein B-48 (ApoB-48). Chylomicrons deliver triglycerides to peripheral tissues, such as adipose and muscle, through the action of lipoprotein lipase (LPL), which is activated by apolipoprotein C-II (ApoC-II). Apolipoprotein C-III (ApoC-III) acts as an inhibitor of LPL activity and the hepatic clearance of triglyceride-rich particles, thereby modulating plasma triglyceride levels. After triglyceride depletion, chylomicron remnants enriched in apolipoprotein E (ApoE) are taken up by the liver. **Red arrows represent the endogenous pathway**, in which the liver synthesises and secretes very-low-density lipoproteins (VLDL), containing ApoB-100 and triglycerides. As VLDL particles are hydrolys by LPL, they are progressively transformed into intermediate-density lipoproteins (IDL) and, subsequently, into low-density lipoproteins (LDL). LDL particles, enriched in cholesterol, deliver cholesterol to peripheral tissues via LDL receptors that specifically recognise ApoB-100. **Green arrows indicate the reverse cholesterol transport pathway**, a key mechanism for maintaining cholesterol homeostasis. High-density lipoprotein (HDL) is synthesised in a nascent, discoidal form (pre-\(\beta\) HDL) by the liver and intestine, incorporating ApoA-I. HDL acquires cholesterol from peripheral tissues via the ATP-binding cassette transporter A1 (ABCA1). Cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT), leading to the formation of mature, spherical HDL.