Albumin-Bound Fatty Acids Modulate Endogenous Angiotensin-Converting Enzyme (ACE) Inhibition

<b>Background/Objectives</b>: Human serum albumin (HSA) is a major endogenous inhibitor of angiotensin-converting enzyme (ACE) and helps fine-tune the activity of the renin-angiotensin-aldosterone system (RAAS), thereby potentially influencing the development of cardiovascular (CV) diseases. As the principal transport protein for free fatty acids (FFAs), HSA may have its ACE-inhibitory capacity modified by its FFA cargo and, through this mechanism, may also affect CV disease risk. We therefore tested the hypothesis that the composition of HSA-bound FFAs determines the magnitude of endogenous ACE inhibition. <b>Methods</b>: We quantified endogenous ACE inhibition and examined the effect of FFA concentration on this inhibition in clinical patients (n = 161 and n = 101, respectively). We measured the effects of HSA treated with saturated, monounsaturated, and polyunsaturated FFAs, as well as FFA-free HSA, on recombinant ACE and on tissue ACE. <b>Results</b>: Endogenous ACE inhibition was stronger in patients with higher serum HSA concentrations (Spearman's rho = 0.422, 95% CI 0.281-0.544, <i>p</i> < 0.001), whereas total FFA concentration was not associated with endogenous ACE inhibition (Spearman's rho = 0.088, <i>p</i> = 0.38, n = 101). However, removal of free fatty acids substantially worsened the ACE-inhibitory effect of HSA on recombinant ACE (charcoal-treated HSA: IC₅₀ = 23.24 [19.40-29.78] g/L vs. control HSA: 7.84 [6.58-9.75] g/L, <i>p</i> < 0.001) and on tissue ACE isolated from lung, heart, and lymph node. FFA chain length, degree and position of unsaturation, and cis/trans configuration all differentially modulated endogenous ACE inhibition. Among saturated fatty acids, stearic acid (IC₅₀ = 7.98 [7.04-9.23] g/L), and among omega-3 and omega-6 fatty acids, α-linolenic (IC₅₀ = 5.60 [4.28-6.15] g/L) and γ-linolenic acids (IC₅₀ = 5.09 [4.28-6.15] g/L) produced the greatest enhancement of the ACE-inhibitory capacity of HSA. <b>Conclusions</b>: The present results indicate that HSA concentration relates to endogenous ACE inhibition in serum, and in vitro experiments demonstrate that HSA-bound FFAs can modulate HSA-mediated ACE inhibition, a mechanism that may be relevant to cardiovascular physiology and disease.