Tissue-specific relaxin-2 is differentially associated with the presence/size of an arterial aneurysm and the severity of atherosclerotic disease in humans

Abstract

Circulating or tissue-related biomarkers are of clinical value for risk stratification in patients with abdominal aortic aneurysms. Relaxin-2 (RL2) has been linked to the presence and size of arterial aneurysms, and to the extent of atherosclerosis in human subjects. Here, we assessed the expression levels of RL2 in aneurysmal (AA, n = 16) and atherosclerotic (ATH, n = 22) arteries, and established the correlation between RL2 levels and the presence/size of AA and the clinical severity of atherosclerosis. The expression levels of metalloproteinases (MMPs) and endothelial nitric oxide synthetase (eNOS) were also detected for correlations with different phenotypes of atherosclerosis and AA. Temporal artery biopsy specimens ( n = 6) and abdominal aortic tissues harvested from accident victims during autopsy ( n = 10) were used as controls. Quantitative tissue biomarker analysis revealed that tissue-specific RL2 was increased in patients with larger or symptomatic AA compared to subjects with atherosclerotic disease and healthy controls. In situ RL2 levels were proportional to the size and the severity of aneurysmatic disease, and were substantially elevated in patients with symptomatic aneurysm of any diameter or asymptomatic aneurysm of a diameter >350% of that of the normal artery. In contrast, tissue RL2 was inversely associated with the clinical severity of atherosclerotic lesions. Correlation between RL2 and MMP2 was different between ATH1 and ATH2, depending on atherosclerosis grade. Overall, tissue RL2 is differentially associated with discrete phenotypes of arterial disease and might exert multipotent biological effects on vascular wall integrity and remodeling in human subjects.

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases

“…Serum levels of relaxin-2 are higher in the early stages of atherosclerosis and gradually decrease with the progression of the disease, eventually showing comparable results between patients with permanent ischemic manifestations from target organs and healthy subjects ( Table 4 ) [ 134 ]. Supporting these findings, an inverse association of arterial tissue relaxin-2 mRNA levels with the clinical severity of atherosclerotic lesions was recently reported [ 170 ]. Tissue relaxin-2 mRNA levels are inversely correlated with MMP-2 in mild atherosclerosis and positively correlated with eNOS in moderate atherosclerosis, which supports the beneficial effect of relaxin-2 in this pathology [ 170 ].…”

“…Supporting these findings, an inverse association of arterial tissue relaxin-2 mRNA levels with the clinical severity of atherosclerotic lesions was recently reported [ 170 ]. Tissue relaxin-2 mRNA levels are inversely correlated with MMP-2 in mild atherosclerosis and positively correlated with eNOS in moderate atherosclerosis, which supports the beneficial effect of relaxin-2 in this pathology [ 170 ]. Recently, Klimontov et al (2022) found no associations between serum levels of relaxin-2 and carotid atherosclerosis in patients with type 2 diabetes (T2D) [ 171 ].…”

“…Moreover, clinical studies have described that IL-6 serum levels are elevated during unstable angina and are considered an independent risk factor for coronary artery disease, suggesting the use of IL-6 as a biomarker for evaluating the inflammatory response and severity of the disarrangements arising from atherosclerosis [ 168 , 169 ]. In this context, it is conceivable to hypothesize that relaxin-2 may be involved in several vascular diseases such as atherosclerosis, despite the lack of recent reports deciphering the specific role of relaxin-2 during the atherosclerotic process [ 133 , 166 , 170 ].…”

Carotid Artery Disease in Subjects with Type 2 Diabetes: Risk Factors and Biomarkers

“…Previous studies revealed decreased serum levels of relaxin in patients with T2D, with inconsistent data on the relationship with glycemic control [ 53 , 54 ]. It was reported that in subjects with CA and PAD, relaxin expression in the arterial walls, as well as serum relaxin levels, is inversely associated with the severity of atherosclerotic lesions [ 55 , 56 ]. Nevertheless, in our patients, we found no association between relaxin and CA.…”

Sex Differences in Inflammation During Venous Remodeling of Arteriovenous Fistulae

“…Notably, the relaxin family of hormones upregulates MMP-2 and MMP-9 expression to contribute to vessel remodeling (62,63), suggesting that relaxin-relaxin receptor signaling might be a significant contributor to the sex differences present during AVF maturation as relaxin and its downstream molecules differ between sexes (64)(65)(66)(67)(68). Knockout of the relaxin receptor resulted in decreased outward remodeling in a murine model of AVF failure, accompanied by increased elastin content, reduced elastase activity, increased CD45+ leukocytes, and increased MCP-1 expression (69).…”