The Protective Role of Interleukin-37 in Cardiovascular Diseases through Ferroptosis Modulation.

The role of ferroptosis and iron metabolism dysregulation in the pathophysiology of cardiovascular diseases is increasingly recognized. Conditions such as hypertension, cardiomyopathy, atherosclerosis, myocardial ischemia/reperfusion injury, heart failure, and cardiovascular complications associated with COVID-19 have been linked to these processes. Inflammation is central to these conditions, prompting exploration into the inflammatory and immunoregulatory molecular pathways that mediate ferroptosis and its contribution to cardiovascular disease progression. Notably, emerging evidence highlights interleukin-37 as a protective cytokine with the ability to activate the nuclear factor erythroid 2-related factor 2 pathway, inhibit macrophage ferroptosis, and attenuate atherosclerosis progression in murine models. However, a comprehensive review focusing on interleukin-37 and its protective role against ferroptosis in CVD is currently lacking. This review aims to fill this gap by summarizing existing knowledge on interleukin-37, including its regulatory functions and impact on ferroptosis in conditions such as atherosclerosis and myocardial infarction. We also explore experimental strategies and propose that targeting interleukin-37 to modulate ferroptosis presents a promising therapeutic approach for the prevention and treatment of cardiovascular diseases.

Association of the IL-37 Polymorphisms with Transaminases and Alkaline Phosphatase Levels in Premature Coronary Artery Disease Patients and Healthy Controls. Results of the Genetics of Atherosclerotic (GEA) Mexican Study.

Interleukin 37 (IL-37) is an anti-inflammatory cytokine expressed in foam cells located in the atherosclerosis plaques. The present study aimed to evaluate the association of the IL-37 polymorphisms with premature coronary artery disease (pCAD), cardiovascular risk factors, metabolic parameters, and levels of liver enzymes. Three IL-37 polymorphisms (rs6717710, rs2708961, and rs2708947) were determined in 1161 patients with pCAD and 951 healthy controls. IL-37 polymorphisms were not associated with the presence of pCAD. The association of the polymorphisms with cardiovascular risk factors, metabolic parameters, and levels of liver enzymes was evaluated independently in pCAD and healthy controls. In pCAD patients, under different models, the rs6717710 was associated with low risk of having elevated alkaline phosphatase (ALP) (padditive = 0.020; pdominant = 0.02; pheterozygous = 0.04; pcodominant1 = 0.040). On the other hand, in healthy controls, the rs6717710 was associated with low risk of having elevated levels of alanine aminotransferase (ALT) (padditive = 0.04, precessive = 0.01, pcodominant2 = 0.01) and aspartate aminotransferase (AST) (padditive = 0.02, pdominant = 0.02). The IL-37 polymorphisms were not associated with the risk of pCAD. In pCAD patients, the rs6717710 was associated with low risk of having elevated ALP levels, whereas in controls was associated with low risk of having elevated ALT and AST levels.

IL-37 Gene and Cholesterol Metabolism: Association of Polymorphisms with the Presence of Hypercholesterolemia and Cardiovascular Risk Factors. The GEA Mexican Study.

Interleukin 37 (IL-37) is an anti-inflammatory cytokine involved in the regulation of cholesterol homeostasis, reducing the levels of plasma cholesterol, fatty acids, and triglycerides. The aim of the present study was to evaluate the association of the IL-37 polymorphisms with the presence of hypercholesterolemia (HC), and with cardiovascular risk factors. Nine IL-37 polymorphisms (rs2708965, rs2708962, rs6717710, rs2708961, rs2708960, rs2708958, rs2723187, rs2708947, and rs2723192) were determined by TaqMan assays in a group of 1292 individuals (514 with and 778 without hypercholesterolemia) belonging to the cohort of the GEA Mexican Study. The associations were evaluated by logistic regression, using inheritance models adjusted by confounding variables. Under codominant 1 model, the rs2708961 (OR = 0.51, p = 0.02), rs2723187 (OR = 0.35, p = 0.005), and rs2708947 (OR = 0.49, p = 0.02) polymorphisms were associated with low risk of HC. The association of the polymorphisms with cardiovascular risk factors was evaluated independently in HC and non-HC individuals. In non-HC individuals, some polymorphisms were associated with the risk of having high levels of LDL-C, glucose, and high risk of T2DM, and low risk of having high visceral abdominal fat. On the other hand, in individuals with HC five, polymorphisms were associated with high levels of C-reactive protein. The IL-37 rs2708961, rs2723187, rs2708947 polymorphisms were associated with low risk of HC, and some IL-37 polymorphisms were associated with cardiometabolic factors in both individuals with and without HC.