The role of leptin in the pathogenesis of atherosclerosis

Knowledge of the pathogenesis of atherosclerosis is critical to the successful fight against cardiovascular diseases. More and more attention has been paid to adipose tissue with its ability to synthesize biologically active substances of a hormonal type. The role of fat cells in the development of inflammation and their ability to control inflammation at the immune and neuroendocrine levels deserves attention. Inflammation leads to the debut of atherosclerotic changes and metabolic syndrome. You will learn from the article about the role of leptin in this process.


  1. The meaning of atherosclerosis.
  2. The main provoking factors.
  3. Systemic violations.
  4. Final results.

The meaning of atherosclerosis

Atherosclerosis was seriously discussed at the beginning of the last century for the first time. It is a different combination of changes in the vascular endothelium and blood components under the influence of accumulation of lipids, complex carbohydrates, fibrosis, and calcification. In fact, this is a typical pathological process. Fats enter the digestive system, where they are broken down into fatty acids and individual glycerides under the action of enzymes. After that, resynthesis of triglycerides occurs in the epithelial cells of the intestine, and they enter the lymph as part of lipoproteins. Fatty acids are oxidized in cellular mitochondria.

The combination of maximum cholesterol with a minimum of lipoprotein lipase becomes a trigger for hyperlipoproteinemia. It causes the formation of low-density lipoproteins in the form of a plaque together with injury to the walls of blood vessels. Over time, its structure changes: fats are deposited in it and an inflammatory reaction. An immune nature develops in result. It plays the role of a chemokine (engine) for smooth muscles and bioactive substances.

Thus, atherosclerosis should be considered as a polyetiological pathology, which is easier to prevent than to treat.

The main provoking factors

Several provocative factors are involved in the development of atherosclerosis. Here are just the main ones.

Inflammatory reactions

Local inflammation occurs due to the accumulation of lipids in the vascular wall: macrophages migrate to the lesion focus, accumulating in the vascular initme. Over time, the endothelium is replaced by connective tissue that bulges into the vessel lumen. Inflammation stimulates the proliferation of smooth muscles in parallel.

Macrophages start expressing receptors that inactivate microbes associated with atherosclerosis. There are:

  • cytomegaloviruses;
  • Chlamydia pneumoniae;
    periodontal microflora: Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis;
  • Helicobacter pylori.

They support macrophages, inflammation, and atherosclerotic plaque strength. When microorganisms come to the blood, they activate B-lymphocytes and trigger the production of antibodies. They are similar in structure to antibodies that are obtained when LDL is oxidized and captured by macrophages. Inflammation in atherosclerosis is controversial: on the one hand, its goal is to stabilize the atherosclerotic plaque, on the other hand, there is a constant risk of its destabilization. Systemic inflammation also contributes to the development of atherosclerosis. It leads to a higher risk of developing atherosclerosis, regardless of other provoking factors, and in itself changes the lipid spectrum.

Oxidative stress

Exotoxins are risk factors for the development of atherosclerosis. They can lead to the formation of free radicals, which in turn provokes damage to the DNA of smooth muscle cells. They are capable of phagocytosis and transformation into foam cells. Myeloperoxidase is activated in macrophages of atherosclerotic plaques. Oxidative stress and shortening of leukocyte telomeres testifies in favor of a genetic predisposition to the development of atherosclerosis.


Researchers has established an association between polymorphic TLR receptor genes and the risk of myocardial infarction and stroke. TLRs themselves are innate immune receptors. The level of tumor necrosis factor alpha, interleukins, heat shock protein, and fibrinogen increases during the development of atherosclerosis. The association of sex, age, cardiovascular pathologies and gene polymorphism also has been revealed. An important role in the development of atherosclerosis is played by the system of genes that control immune inflammation, metabolism, angiogenesis, and remodeling of the heart and blood vessels. Their activation causes a decrease in insulin resistance, which minimizes atherogenic hyperlipidemia. Some somatic mutations are also involved in the development of atherosclerosis.

Thus, complex gene chains are regulators of cytokine activity. They create a certain level and direction of the inflammatory response.

Systemic violations

We are talking about the metabolic syndrome, neuroendocrine disorders, changes in lipid metabolism, humoral immunity, and changes in the bloodstream, chronic stress and some other nuances. This is where leptin plays a big role.

Disproportion of blood fats

This is a special case of metabolic changes associated with obesity. Lipids perform the functions of endocrine glands and immunity, strongly influence the development of atherosclerotic disease. Their main tasks are considered to be lipolysis and lipogenesis through the synthesis of bioactive substances, including leptin. For example, they stimulate inflammatory reactions of the immune nature through the release of inflammatory cytokines into the blood, control the sympathetic nervous system through arterial hypertension, and an increase in heart rate.

Their level in the bloodstream affects steroids. The connection between high level of leptin and an increased concentration of low-density lipoproteins, total cholesterol and a drop in the concentration of high-density lipoproteins on the background of obesity has been scientifically proven. The level of leptin is directly proportional to the degree of obesity.

Violation of the synthesis and breakdown of lipids in the blood

A key role in atherosclerotic disease belongs to dyslipoproteinemia. It controls the level of high or low density lipoproteins. Various mutations cause a decrease in HDL, provoke the risk of early atherosclerosis, and aggravate its course. It is worth noting familial hypercholesterolemia. Special registries of patients with this pathology have been created in the EU since they are characterized by a hundredfold increase in the risk of death from coronary insufficiency and a tenfold increase in overall mortality. Active screening of relatives helps to reduce such mortality. Today, such registers appear also in the Russian Federation.

Gene mutations regulate the level of triglycerides, which are an independent marker of the development of atherosclerosis. The mechanism of their regulation is implemented through the inactivation of very low density lipoproteins, which are considered the main carrier of triglycerides and activate lipoprotein catabolism. One of the products of lipid peroxidation is malondialdehyde. It is a highly toxic metabolite, a marker of oxidative stress. Its level correlates with the index of vascular dysfunction and the degree of atherosclerosis.

Insulin resistance syndrome

This pathology exacerbates the course of many processes including atherosclerotic.But it is not an independent disease. The variability of the metabolic syndrome  is interesting, it depends on the localization of atherosclerotic changes. Thus, atherosclerosis of peripheral vessels is accompanied by hypertriglyceridemia without obesity. Hypertriglyceridemia and arterial hypertension occur when the carotid arteries are involved in the process. The combination of atherosclerosis of the carotid and coronary arteries without great vessels is combined with arterial hypertension, obesity and hypercholesterolemia. Oxidative stress predominates in patients with multifocal coronary atherosclerosis,

Adipose tissue between epicardium and myocardium

Researchers have noted the affiliation of the concentration of the fatty layer between the cardial layers and atherosclerosis of the carotid arteries. Epicardial adipose tissue as the HUB of fat cells,  synthesizes pro-inflammatory cytokines. It grows due to increased energy, impaired glucose, and insulin metabolism. The severity of the development of fat between the cardiac layers is directly proportional to the risk of developing carotid atherosclerosis.


As a rule, the constancy of the internal environment ensures the norm of lipids in the blood. The level of total cholesterol decreases with anemia. It also affects endothelial dysfunction, which plays an important role in the development of atherosclerosis. The more severe the anemia, the more pronounced the endothelial dysfunction. Thus, atherosclerosis is directly related to tissue hypoxia, which provokes the formation of superoxide radicals and reduces the antioxidant potential of the blood, aggravating dyslipidemia and endothelial dysfunction.

Humoral immunity

Atherosclerosis is supported by inflammation, which affetcs humoral homeostasis, leading to a change in the secretory activity of neutrophils, which synthesize cholesterol-binding proteins in the vascular wall. Neutrophil imbalance leads to activation of lipid release from leukocytes. In addition, monocyte shifts also occur.  Monocytes penetrate into the intima of the arteries with the development of atherosclerosis. They are transformed into foam cells, enriched with lipids and lipoproteins, differentiate into macrophages, absorbing lipids. Monocytes in atherosclerosis actively accumulate gangliosides for the formation of cholesterol, which is involved in the processes of adhesion, reception, cell mobility, and apoptosis.

Calcium and phosphorus metabolism

Atherosclerosis is associated with the level of phosphorus-calcium metabolism. It is believed that atherosclerosis and coronary calcification are two sides of the same coin. Plaque calcification is an unfavorable marker of complications. Changes in calcium homeostasis is associated with atherosclerosis and dyslipidemia have a pattern: the concentration of triglycerides is higher than normal, as is the level of LDL in men with atherosclerosis of the coronary arteries.

Psycho-emotional overstrain

The long-term preclinical development of atherosclerosis is associated with chronic stress. It provokes endothelial dysfunction, through a violation of nitrogen-dependent vasodilation. Endothelial cells activate cytokines and adhesion proteins which cause minimal changes in the atherosclerotic plaque by binding to receptors localized on the surface of monocytes. Oxidizing cholesterol, monocytes are transformed into macrophages, participating in inflammation, forming plaque instability.

Smooth muscle and endothelial dysfunction

Atherosclerosis is provoked by dysfunction of smooth muscles and endothelium. This pathogenesis is genetically determined. There are very few protein-coding genes in the human genome, and only non-coding RNA has been sufficiently studied. Previously, it was believed that it has no function, but now it is clear that this nucleic acid plays a large role in carcinogenesis and chronic pathologies. For example, it is able to inhibit the development of atherosclerosis and stabilize vascular plaques through the expression of macrophages.

There is also a stimulation of low-density lipoproteins, rapid division of smooth muscle cells, the development and progression of atherosclerosis is suppressed via RNA,.

Antigenic system of blood

This is the most important body system, represented by antigens A and B on the surface of red blood cells. Patients with a zero blood group are less at risk of cardiovascular pathologies. The mechanism for this is not entirely clear. Probably everyone who has the first group is the owner of thin-capped atherosclerosis plaques, which is a sign of their instability. In addition, this blood type is correlated with low C-reactive protein. The presence of A and B antigens on the surface of erythrocytes corresponds to a high concentration of total cholesterol and LDL. It corresponds to an individual trigger for the formation of plaques in the coronaries.

Final results

It turns out that the atherosclerotic process accompanies a person all his life. The pathogenesis of this condition is multietiological. The finding of new links in pathogenesis, the formation of registries of patients with familial atherosclerosis can help in the development of new diagnostic methods, differentiation of pathology stages. It can lead to a decrease in morbidity and mortality.

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