Atherogenic Endothelial Cell eNOS and ET-1 Responses to Asynchronous Hemodynamics are Mitigated by Conjugated Linoleic Acid

Abstract

Although local wall shear stress (WSS) induced by blood flow has been implicated in atherogenesis, another prominent and often neglected hemodynamic feature, circumferential strain (CS) driven by pressure, is induced concurrently. To investigate endothelial cell (EC) responses to pathologic hemodynamics and their possible manipulation by pharmaceuticals, we simulated complete hemodynamic conditions comprised of simultaneous WSS and CS during treatment with conjugated linoleic acid (CLA), a known PPAR (-alpha and -gamma) activator and anti-atherogenic agent, on cultured EC and examined effects on gene and metabolite expression. Two hemodynamic conditions representative of distinct regions of the circulation, coronary arteries: pro-atherogenic (asynchronous WSS and CS) and straight descending aorta: non-atherogenic (synchronous WSS and CS), were applied to cultured EC during treatment with the nutraceutical CLA. Competitive-quantitative RT-PCR showed that asynchronous hemodynamics significantly reduced ( approximately 2-fold) eNOS and PPAR-gamma mRNA levels compared to synchronous hemodynamics at 5 and 12 h. ET-1 showed an opposite trend at 12 h. CLA treatment mitigated pro-atherogenic eNOS, ET-1, PPAR-alpha and -gamma mRNA expression profiles and NO and ET-1 secretion patterns during asynchronous hemodynamics. This study demonstrates the potential for a pharmacological treatment (CLA) to normalize pro-atherogenic gene expression profiles induced by hemodynamics inherent to the circulation.

Concentration and Time Effects of Dextran Exposure on Endothelial Cell Viability, Attachment, and Inflammatory Marker Expression In Vitro

“…4,5,[11][12][13]17,22,24,[35][36][37] In endothelial cell hemodynamic studies, dextran is often used to help match values of blood viscosity and density. Despite the known effects of dextran on cells and its use in the isolation of blood components, it is often assumed in endothelial cell hemodynamic studies that the effects of neutral dextran are negligible.…”

“…In this work, we chose a dextran molecular weight in the range used in perfusion dynamic cell studies (MW 135,000), 12 concentrations up to 17.5%, above the range normally used which varies from 1% w/w 16,17 and 9.5% w/w. 12,13,37 Molecular weights up to 2 million and concentration up to 30% w/w have been shown to have a Newtonian behavior. 1,8,43,48 The viscosity values we obtained compare well with literature data, Fig.…”

“…Dextran has often been used for this as it is believed to have little side effects. 5,12,13,37,46 It has been used in other applications because of its effects on blood components. 6,7 Clinically, low molecular weight dextran (MW 40,000) is used to expand blood volume and reduce blood clotting, 15,51 hence reducing risks of thrombosis and as an anticoagulant.…”

eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues

“…Indeed, coronary arteries have reduced eNOS mRNA levels compared with aortic regions, whereas endothelin mRNA shows an opposite trend (88). Fully reversing shear stress is known to inhibit eNOS activation and NO release while enhancing oxidative stress (125).…”

Turning Meat, Poultry, Eggs, and Dairy Products Into Nutraceuticals Through Increasing Their Conjugated Linoleic Acid Levels, Part One: Reviewing the Literature of Benefits Claimed for Conjugated Linoleic Acids in Human Health

“…It found that one widely theorized view of the mode of action of CLAs (Wähle and Rotondo 1999) in reducing atherogenesis (based on some studies of CLA causing cancer cells to lose a degree of their self-adhesion powers), by having CLAs cause a reduction in the ability of unwanted or damaged blood cells, blood products, or blood cellular debris to stick together, was disproven and must now be seen as an unlikely pathway for any purported CLA reductions in cardiovascular inflammation or clotting. An alternative explanatory mechanism-an ability for CLAs to enable blood vessels to withstand adverse blood flow and blood pressure fluctuations as seen in heart attacks and strokes-has since been proposed (Dancu et al 2007). In any case, Eder et al (2003) have demonstrated that CLAs lower the cascade of "damage alarm" substances (like nitrous oxide) in the cells lining the human aorta-an important benefit because their uncontrolled release actually tends to exacerbate rather than improve cardiovascular inflammation.…”