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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])