Table 5 Overview of the proteins differentially expressed between sexes
From: Sex differences in circulating proteins in heart failure with preserved ejection fraction
Individual biomarker | Mechanistic significance | Previous relevant reports | Reports on sex differences | ||
|---|---|---|---|---|---|
Basic reports | Clinical reports | Healthy population | Heart disease | ||
More highly expressed in females | |||||
IL1RL2 | Activates pro-inflammatory pathways upon binding of IL-36 [23] | Involved in inflammatory diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis [23] | No | No | |
LPL | Enzyme that catalyzes the hydrolysis of triglycerides | Overexpression or downregulation of cardiac LPL in diabetic mouse models resulted in impaired left ventricular function [24]. | Associated with coronary heart disease, Alzheimer disease, and chronic lymphocytic leukemia [25] | No | No |
LHB | Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids | Levels not different between CAD and control subjects [26] | Yes (higher in females vs. males [26]) | Yes (higher in female vs. male CAD patients [26]) | |
IGFBP3 | Most abundant carrier protein for insulin-like growth factor 1 (IGF-1) which is known to play a major role in metabolism | The IGF system (including IGFBP3) has been previously associated with cardiovascular disease and many cancers [27, 28] | In HFpEF patients, low IGF-1 and IGFBP3 were associated with increased parameters of left atrial size and volume [29]. Higher IGF-1 after an acute MI was associated with improved clinical outcomes and echocardiographic measures (LV dimensions, mass, and ejection fraction) [30] | Yes (numerically higher in female vs. male but no formal comparison made [31]) | No |
PLIN1 | Surface protein of adipocyte lipid droplets that regulates storage and hydrolysis of adipose triglycerides [32] | Linked to endocrine metabolism disease (diabetes, obesity etc.), cancers, and cardiovascular disease [33] | Higher expressed in the right atria of patients with CAD compared to those without [34] | No | No |
Ep-CAM | Transmembrane glycoprotein expressed in epithelium | Involved in various processes such as cell signaling, cell-cell adhesion, proliferation and differentiation, tumorigenesis, and metastasis of carcinomas [35] | Not associated with adverse cardiovascular outcomes in a registry of 263 chronic heart failure patients [36] Associated with inflammatory bowel disease [35] | No | No |
Less expressed in females | |||||
NRP1 | Transmembrane receptor for class III semaphorins and for members of the vascular endothelial growth factor family [37] | Neuronal and vascular development during embryogenesis, angiogenesis, and maintenance of vascular integrity [38] | Associated with poor outcome in HFpEF but not in HFrEF patients [39] | No | No |
MMP-3 | Enzyme involved in the breakdown of extracellular matrix proteins | Involved in physiological (e.g. embryogenesis) and pathophysiological (e.g. tumor metastasis and atherosclerosis) processes [40] | Conflicting data: high levels have been described in atherosclerotic plaques [41] and associated with poor outcome after MI [42]. However, a common mutation in the MMP-3 promoter (which results in decreased MMP-3 expression) was associated with atherosclerosis development [43] | No | Yes (higher in male vs. female patients post-MI [42]) |
ACE2 | Hydrolyses angiotensin I and angiotensin II generating angiotensin (1-9) and angiotensin [1,2,3,4,5], respectively. | ACE2 levels were higher in patients with type 1 diabetes and coronary heart disease vs. controls [44] | Yes (conflicting data: similar levels in male and females [45] or higher in male vs. female [44]) | Yes (higher in males vs. females with type 1 DM and CAD [44]) | |