Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 3 • June-July 2011

Mechanisms Underlying the Adverse Effects of HDL from Patients with Coronary Artery Disease As Compared to HDL from Healthy Individuals

As we have written in earlier newsletters, all HDL is not the same. While increased levels of HDL are generally protective against the risk of cardiovascular disease, under some conditions HDL loses its protective effects and actually PROMOTES cardiovascular disease. A July 2011 paper1 explores mechanisms to explain adverse effects of HDL from patients with coronary artery disease. The results are informative but, more important, point to ways to help prevent the loss of protective effects of HDL.

The protective effects of HDL have been found to include promoting the efflux of cholesterol from macrophage foam cells in atherosclerotic plaques, to stimulate endothelial nitric oxide production (that is critical for maintaining healthy endothelial function in blood vessels), and also promotes endothelial repair mechanisms. A number of biochemical pathways have been identified by which HDL performs these protective functions. As the authors1 note: “... endothelial dysfunction, particularly reduced endothelial NO [nitric oxide] bioavailability, is considered to play a key role in the initiation and progression of atherosclerosis and its clinical complications.”

“... the capacity of HDL to mediate cholesterol efflux [export] from lipid-laden macrophages has been observed to be impaired after substantial oxidative modification of HDL by myeloperoxidase or malondialdehyde, a lipid peroxidation product, as observed in atherosclerotic plaques. In addition, the capacity of HDL to prevent the proinflammatory effect of LDL, i.e., LDL-induced monocyte chemotactic activity, was impaired in patients with CAD [coronary artery disease].” Hence, the purpose of this study was to compare the effects of HDL from patients with stable CAD [coronary artery disease], HDL(cad), or acute coronary syndrome with those of HDL from healthy subjects, HDL(healthy), and to investigate mechanisms to explain these differences.

One of the differences, for example, was that increasing concentrations of HDL(healthy) augmented endothelial cell NO production, whereas no such effects were observed with HDL(cad). The authors explain that “[a]ctivation of eNOS in response to HDL(healthy) has been shown to be dependent on Akt-mediated eNOS Ser1177 phosphorylation, a well-known e-NOS activating pathway. We observed that HDL(healthy) but not HDL(cad) stimulated endothelial Akt phosphorylation at Ser473 and Akt-dependent phosphorylation of eNOS at Ser1177.”

The authors report that recent studies suggest that HDL from healthy subjects promotes endothelial repair. They therefore examined HDL(cad) as compared to HDL(healthy) on in vivo endothelial repair in a nude mouse model with carotid artery injury. “Administration of HDL(healthy) accelerated endothelial repair responses within 3 days after carotid injury.” However, “... treatment with HDL(cad) compared with buffer failed to significantly promote endothelial repair ...”

Some of the results indicated that increased production of MDA (malondialdehyde, a lipid peroxidation product) caused modification of HDL that could be responsible for some of the adverse effects of HDL(cad) on endothelial NO production. Notably, the authors explain, PON1, an enzyme associated with HDL, has been reported to prevent MDA formation in HDL.

PON1 activity was found to be substantially reduced in HDL(cad) as compared with HDL(healthy), even though the content of PON1 was increased in HDL(cad) as compared with HDL(healthy).This, suggest the authors, implies that the PON1 in HDL(cad) is inactivated. The authors here note (no reference given) that a human study of extended-release niacin therapy was associated with significantly increased HDL PON1 activity. This is good news, but keep in mind that the potential for liver toxicity is increased in some people by extended-release niacin as compared to ordinary niacin. Hence, if you want to take extended-release niacin or ordinary niacin at doses of 800 mg per day or more, it is essential that you have your doctor order liver tests to detect any potential liver toxicity. In another study, supplementation of HDL from patients with CAD with purified PON1 partially improved the capacity of HDL to stimulate endothelial NO production under physiological conditions.

“... in experimental studies PON1 has been observed to prevent atherosclerotic lesion development and in recent clinical studies reduced serum activity of paraoxonase [PON] was associated with increased cardiovascular risk.” The authors conclude that “[t]he present study for the first time to our knowledge provides evidence that HDL-associated PON1 activity plays a role in maintaining the endothelial-atheroprotective effects of HDL ...”

Natural Products That Have Been Reported To Increase PON1 Activity

The good news is that there have been reports of increased PON1 activity by various natural products in peer-reviewed published scientific papers. For example, one study2 reported that POMEGRANATE JUICE polyphenols increased recombinant paraoxonase-1 (PON1) binding to HDL in plasma collected from six male patients with type 2 diabetes mellitus after they drank 50 mL of concentrated pomegranate juice daily for a period of 4 weeks. The results indicated that PJ increased the capacity of HDL to bind rePON1 (recombinant PON1) not only in vitro, but in vivo. As the authors2 noted, PON1 activity has been shown to be reduced in patients with type 2 diabetes and, in these patients, a more severe coronary artery disease was observed by coronary angiography.

Another paper3 reports that the paraoxonase- (PON1) gene expression was induced (>2 fold increase in PON-1 mRNA levels) by RESVERATROL in a study of cell cultures. These authors note that “[b]oth WINE consumption and the isolated flavonoids QUERCETIN and CATECHIN increase serum PON1 activity in human and mice. We recently reported that quercetin, a partial agonist of the aryl hydrocarbon receptor ... induce the PON-1 gene expression.” Quercetin is naturally enriched in onions. Both our high-potency muti-vitamin/mineral/antioxidant formulations contain quercetin, and catechin is found in tea, especially white and green tea, and is also included in our special teas and EGCG booster formulation.

Another natural product reported to protect PON-1 from free radical inactivation is extract of Ilex paraguariensis (YERBA MATE).4 In this study, healthy volunteers drank either 0.5 L of IP (yerba mate) extract, 0.5 L of coffee and milk or nothing. PON-1 activity was reported to increase an average of 10% with yerba mate extract ingestion above the changes seen when the intake was coffee and milk (p <0.05). As the authors note, “[t]he magnitude of the effect [increased activity of PON-1], although modest, is similar to that found for statins or other polyphenol-containing beverages.” Moreover, the authors explain, “[s]everal communications from our laboratory and from other authors show that Ilex paraguariensis extracts are potent inhibitors of LDL oxidative modifications, cell oxidative stress and atherogenesis in a rabbit model.” “Chlorogenic acid and its isomers constitute the major polyphenolic fraction of mate tea.”

BUT DON’T EAT THIS ... Meanwhile, serum paraoxonase activity was reported in another paper5 to be decreased in 12 healthy men (22–63 years of age) after a meal rich in used cooking fat from deep fat frying. If you eat french fries or fried foods at fast food restaurants, you will be getting a lot of it in your food, as the cooking oils are re-used. They found that peroxide content of LDL tended to increase after the used fat meal and tended to decrease after the meal rich in unused fat. These changes were significantly different.


  1. Besler et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 121(7):2693-2708 (2011).
  2. Fuhrman et al. Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients. Nutrition 26:359-66 (2010).
  3. Gouedard et al. Induction of the paraoxonase-1 gene expression by resveratrol. Arterioscler Thromb Vasc Biol 24:2378-2383 (2004).
  4. Menini. Protective action of Ilex paraguariensis extract against free radical inactivation of paraoxonase-1 in high- density lipoprotein. Planta Med 73:1141-7 (2007).
  5. Sutherland et al. Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat. Arterioscler Thromb Vasc Biol 19:1340-7 (1999).

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