Abstract
Background: Apolipoprotein E4 (apoE4) is the most significant risk factor known to cause Alzheimer dementia (AD) [1], but also crucial in atherogenesis as pathological correlative of coronary heart disease (CHD) [2]. Therefore, the present investigation aimed at unveiling the role of LDL-apoE isoforms in vascular reactivity, especially in flow-dilatation of human coronaries. Materials and Methods: Isometric tension was measured in segments of human coronary arteries from heart transplantations changing the superfusate flow rate in the sequence 3, 5, 20, 40 and 100 mL/min. The initial tension was 2 g. Krebs solution without (control) and with addition of 100 mg/dL pooled LDL, LDLapoE4/E4 or LDLapoE0/E0 (from an apoE ‘knockout man’) was used as superfusate. Intracellular recordings of membrane potential and determination of cAMP and cGMP concentrations were carried out. Results: Initial tension at 3 mL/min flow (T 3 ): control 1.649 g, pooled LDL 1.739 g, LDLapoE4/E4 1.773 g, LDLapoE0/E0 1.796 g; flow-dependent Δtension (T 100 - T 3 ): control -0.418 g, pooled LDL -0.263 g, LDLapoE4/E4 -0.197 g, LDLapoE0/E0 +0.313 g. Upon a basal flow rate of 3 mL/min, the initial tension showed a graded course both in normal and in deendothelialized preparations: both pooled LDL (+5.5% vs. +4.7%) and LDLapoE4/E4 (+7.5% vs. +5.6%) as well as LDLapoE0/E0 (+8.9% vs. +10.2%) enhanced mechanical force as compared to the controls. Endothelium-denuded segments had basically a higher tone (+5.2%) on grounds of an impaired basal NO release. Latter preparations demonstrated this graded course especially significant during flow-dependent dilatation, which was reversed to constriction by +109.3% under pooled LDL, by +160.1% under LDLapoE4/E4 and by +332.1% under LDLapoE0/E0 compared with the control. Membrane potentials reflected tension: hyperpolarization of the vascular smooth muscle cells preceded relaxation, depolarization preceded contraction. Relating the membrane potential to the corresponding tone revealed a sigmoidal electromechanical coupling curve. For the first time in literature, we report on a chemomechanical coupling curve by correlating the nucleotide concentration with the corresponding tension. Conclusion: LDLapoE4/E4 reversed flow-dependent vasodilatation to constriction and was only exceeded in its deleterious effect by LDL devoid of any apoE. There is growing evidence that binding of apoE4/E4 and apoE0/E0 to the flow sensor proteoheparan sulfate (endothelial syndecan superfamily) leads to nanoplaque build-up [1,2] at the endothelium-blood interface and thus impairs vascular reactivity.
Published Version
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