CD40/CD40L and Related Signaling Pathways in Cardiovascular Health and Disease—The Pros and Cons for Cardioprotection

Abstract

The CD40–CD40 ligand (CD40L) dyad represents a scientific and clinical field that has raised many controversies in the past and cannot be clearly defined as being an either beneficial or harmful pathway. Being crucially involved in physiological immunological processes as well as pathological inflammatory reactions, the signaling pathway has been recognized as a key player in the development of both autoimmune and cardiovascular disease. Even though the possibilities of a therapeutic approach to the dyad were recognized decades ago, due to unfortunate events, detailed in this review, pharmacological treatment targeting the dyad, especially in patients suffering from atherosclerosis, is not available. Despite the recent advances in the treatment of classical cardiovascular risk factors, such as arterial hypertension and diabetes mellitus, the treatment of the associated low-grade inflammation that accounts for the progression of atherosclerosis is still challenging. Low-grade inflammation can be detected in a significant portion of patients that suffer from cardiovascular disease and it is therefore imperative to develop new therapeutic strategies in order to combat this driver of atherosclerosis. Of note, established cardiovascular drugs such as angiotensin-converting enzyme inhibitors or statins have proven beneficial cardiovascular effects that are also related to their pleiotropic immunomodulatory properties. In this review, we will discuss the setbacks encountered as well as new avenues discovered on the path to a different, inflammation-centered approach for the treatment of cardiovascular disease with the CD40–CD40L axis as a central therapeutic target.

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics

“…We described several potential organ-specific immune system activation patterns, but their effect on organ failure emergence is unclear (46,64,65). The only advent of kidney failure, liver failure, and need for pressors was associated with elevation of specific markers (CCL4, CD40, CXCL5, and IL-15), but our findings' interpretation needs more broad context (66). Elevation in VEGFA and CD28 in patients with kidney failure suggests its involvement in the emergence of this organ failure (58,67).…”

Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia

“…CD40 has been implicated in various disorders, such as atherosclerosis, cardiovascular, metabolic (arterial hypertension, diabetes mellitus, etc. ), and the others [ 68 , 69 ]. Importantly, the CD40 DNA methylation levels [ 70 ] and CD40 expression (protein and mRNA) [ 71 ] were associated with gastric cancer.…”

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19

“…CD40L is also a key player in platelet activation. CD40L and its receptor CD40 are expressed in cells including platelets, endothelial cells, VSMCs, T lymphocytes and macrophages ( Daub et al, 2020 ). Activated, platelets rapidly (within seconds) express CD40L, and the interaction of CD40L and CD40 on endothelial cells up-regulate the cytokines IL-1, IL-8 and IL-6, MCP-1 and adhesion molecules, as well as increasing TF expression ( Antoniades et al, 2009 ).…”