Understanding the Signaling Pathways Governing Atherosclerosis Pathogenesis

Atherosclerosis is a condition where arteries become narrowed due to a build-up of fatty material, usually cholesterol, and other substances such as calcium. This can lead to a range of serious health complications including heart attack or stroke. Risk factors for atherosclerosis include high blood pressure, high cholesterol, diabetes, smoking, and obesity.

As fatty material accumulates in the arteries, a mass can develop which restricts the vessel diameter and hardens into a plaque/atheroma (Figure 1). These plaques carry the dual risk of reducing blood flow locally and splitting from the artery wall. The latter event is the most dangerous as the free plaque can travel to a narrower vessel and obstruct it, exposing patients to a higher risk of heart attack and stroke (1, 2, 3, 4).

Signaling Pathways Involved in Atherosclerosis Development

The primary cellular mechanism at play in atherosclerosis pathogenesis is the renin-angiotensin-aldosterone system (RAAS). RAAS is a hormone system that helps regulate blood pressure and fluid balance in the body. In atherosclerosis patients, this system becomes dysregulated, leading to an increase in blood pressure and a build-up of plaques in arteries.

The RAAS pathway involves several hormones and enzymes, including angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and aldosterone. ACE is an enzyme that converts angiotensin I (Ang I) into the powerful vasoconstrictor Ang II (Figure 2). Beyond vasoconstriction, Ang II stimulates the release of aldosterone, a hormone that helps regulate fluid balance and blood pressure. It also promotes the production of cholesterol and other substances in the arterial wall, leading to plaque formation. Dysregulation of the RAAS pathway and the resulting accumulation of cholesterol and other fatty substances in the arteries is understood to be a leading cause of atherosclerosis development (1, 2, 4, 5).

Another pathway known to contribute to atherosclerosis development is the Wnt signaling pathway. In normal circumstances, Wnt signaling influences cell growth and differentiation, but when this pathway is dysregulated it can lead to an accumulation of cholesterol and fatty deposits in the arteries.

Immune and Inflammatory Mechanisms of Atherosclerosis

Inflammation also plays a significant role in the development of atherosclerosis. Specific immune pathways identified as players in pathogenesis include (1, 5):

• The cyclooxygenase (COX) pathway promotes the production of inflammatory mediators, such as prostaglandins, which can contribute to plaque formation and lead to arterial narrowing. The COX pathway is activated by inflammatory stimuli and can lead to the production of a variety of inflammatory mediators.
• The Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway is activated by inflammatory stimuli and can lead to the production of a variety of inflammatory mediators, such as reactive oxygen species (ROS).
• The Nuclear Factor Kappa B (NF-ΚB) pathway, which is activated by inflammation and promotes the production of inflammatory mediator cytokines.

Inflammatory processes occur in several steps (Figure 3):

• The accumulation of fatty materials like cholesterols (low-density lipoprotein; LDL) promotes local inflammation through lipid oxidation in the artery walls. This triggers the local endothelial cells to release inflammatory cytokines, such as interleukin-1 (IL-1) and TNF-α, in response.
• Circulating tissue-resident macrophages and monocytes get attracted to the fatty deposits and attempt to clear them by phagocytosis. However, the excessive uptake of oxidized LDLs causes the macrophages to die as they lack the ability to process and digest them in large amounts.
• The dead cell remnants, also known as foam cells, accumulate in the arterial walls where they contribute to the development of plaques and increase local inflammation.

In addition, inflammatory cytokines can activate smooth muscle cells, causing them to proliferate, migrate, and secrete extracellular matrix proteins. This can lead to the formation of a fibrous cap which protects the plaque from rupture (and also reduces the risk of a heart attack or stroke). Chronic inflammation in the arterial walls can also trigger the immune system to release additional inflammatory substances in a self-amplifying loop that attracts more immune cells, further contributing to the development of plaques.

Because of the prominent role of inflammation in atherosclerosis development, it must be kept under control to reduce risk. This can be achieved by monitoring factors such as high cholesterol and high blood pressure, as well as eating a healthy diet and exercising regularly. In addition, avoiding smoking can help to reduce the risk of atherosclerosis, as smoking increases inflammation in the body (1, 2).

Therapeutic Strategies for Atherosclerosis

Therapeutic approaches aim to control the risk factors associated with atherosclerosis development. This includes lifestyle changes such as switching patients to healthier diets and exercise regimens to mitigate chronic inflammation and circulation of fatty materials. Patients are often supplemented with medications to keep fatty materials, blood pressure, and potential diabetes in check. In addition, specific medication is indicated in some high-risk patients to reduce potential atherosclerotic vascular events. For example, aspirin or clopidogrel act on blood fluidity to decrease heart attack and stroke risk.

Medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), statins, and non-steroidal anti-inflammatory drugs (NSAIDs) can also be used to target the signaling pathways involved in the pathogenesis of atherosclerosis. Surgical techniques like endarterectomy (removal of plaque from the arterial walls) or stenting (introduction of a tubular structure inside a vessel to keep it open and prevent its obstruction) are reserved for the more severe cases when the state of the atherosclerotic vessel is such that the previously described strategies are not sufficient to eliminate the deposited arterial plaques. However, surgeries on vessels are not always effective and can carry significant risks.

The effectiveness of lifestyle changes and medications in treating atherosclerosis depends on the individual. It is important to keep in mind that the current state of available medications does not allow them to be a substitute for lifestyle modifications. Furthermore, current medications can only address the problem once atherosclerotic tissues develop (4, 5, 6).

Current atherosclerosis research is focused on the mechanisms promoting disease progression and the development of new therapeutic solutions to prevent such progression. Key areas of interest include the role of cholesterol-lowering drugs like statins and monitoring the results achieved by changes in patient lifestyle (exercise, diet, etc.). Pharmaceutical approaches involve exploring the potential of drugs that target the RAAS pathway to inhibit the ACE enzyme and/or block the signaling abilities of Ang II.

There have also been advances in understanding the underlying causes of disease. As such, recent studies have looked at atherosclerosis from a molecular perspective and shone a light on new players in disease pathogenesis. The role of inflammation has notably been re-evaluated as one of the key drivers of disease, and other more obscure factors are suspected to be playing a greater role. Newcomers include epigenetic modifications, such as DNA methylation of genes involved in lipid metabolism, and the link between an inflammatory environment, the gut microbiota, and pro-disease metabolites (1, 2, 3, 5, 6).

References

1. Libby P. Inflammation in atherosclerosis. Nature. 2002 Dec 19;420(6917):868-74.
2. Soehnlein O, Libby P. Targeting inflammation in atherosclerosis – from experimental insights to the clinic. Nat Rev Drug Discov. 2021 Aug;20(8):589-610.
3. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology and treatment of atherosclerosis. Neth Heart J. 2017 Apr;25(4):231-42.
4. Wiebe D. The Cholesterol Wars: The Skeptics vs. the Preponderance of Evidence. Daniel Steinberg. San Diego, CA, Academic Press-Elsevier, 2007, ISBN: 978-0-12-373979-7. Clinical Chemistry. 2009 Jul 1;55(7):1441-2.
5. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007 Oct 16;116(16):1832-44.
6. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults| Circulation [Internet]. [cited 2023 Jan 25].