By Benjamin V. Treadwell, Ph.D.
How many of you remember back four decades ago when the media first bombarded us with dire warnings about the dangers of consuming cholesterol-rich foods, such as eggs and red meat, on a regular basis?
The advice was scary as it made the connection between high levels of cholesterol in our blood and the clogging of arteries and heart disease. Obviously this was bad news for the poultry and cattle farmers who argued there was no compelling evidence showing an association between eating eggs or meat and the increased incidence of heart disease. Could it be that the farmers were, for the most part, correct? It turns out, the cholesterol connection with heart disease is complex. This month’s Juvenon Health Journal explores recent findings that may help you determine the best ways to maintain a healthy cardiovascular system.
HDL: The Good Cholesterol?
Cholesterol is carried in the blood stream and present in the tissues of the body. It is normally combined with different molecular species, predominately proteins. This molecular association imparts different properties to the cholesterol particle, and the most conspicuous property is its density. Two of the most common forms of cholesterol-carrying particles are termed LDLc (low-density lipoprotein) and HDLc (high-density lipoprotein).
LDLc carries cholesterol from the liver, where it is manufactured, to outlying tissues to be utilized for the synthesis of important cellular molecules. These molecules include steroids such as progesterone and testosterone. However, LDLc is susceptible to oxidation, which results in its conversion to LDLox, a toxic-inflammatory molecule. LDLox contributes to heart disease and can be measured as a marker for heart disease.
HDLc, on the other hand, is known as the good or ‘happy’ cholesterol, as it carries cholesterol away from the tissues back to the liver to be excreted in bile.
Recently, HDLc has been shown to have additional positive effects on vascular health, in particular the stimulation of an enzyme endothelial nitric oxide synthase (eNOS), which is involved in the production of nitric oxide. This gaseous molecule relaxes blood vessels, reduces blood pressure and protects the endothelial cells lining our arteries.
The latest research may clarify conflicting reports on the effects of certain therapeutics demonstrated to raise HDLc. Basically, it appears that some HDLc-raising therapeutics improve cardiovascular health, while others may have no effect, or even be detrimental. These varied effects of HDL-raising therapeutics on cardiovascular health have led many in the field to conclude there are different forms of HDLc, and some may not be healthy.
All HDL Is Not Created Equal
Investigators have discovered, after extensive analysis, different forms of HDLc with different associated molecules bound to the core HDL particle. A recent study shows that HDLc in patients with coronary artery disease (CAD) is not equivalent in composition to HDLc in healthy patients of similar age.
Past studies have demonstrated the protective effects HDLc has on the endothelial cells, important cells which line the arteries in a single layer. These delicate - yet hard-working- cells are largely responsible for keeping our arteries healthy and disease-free.
HDLc helps endothelial cells activate an enzyme, eNOS, to produce nitric oxide (NO). The released NO diffuses into the smooth muscle cells within the artery wall. This action in turn signals the muscle to relax, lowering blood pressure, and improving circulation. Importantly, nitric oxide prevents inflammation that can lead to atherosclerosis and heart disease.
This is the normal healthy effect of HDLc on the endothelial cells from normal, healthy patients. Still, scientists were curious about how the endothelial cells of patients with heart disease react to HDLc. The experimental results astonished the investigators. They discovered that the HDLc taken from CAD patients, and placed in a culture dish containing endothelial cells did not stimulate the beneficial eNOS release that occurs with HDLc isolated from normal healthy patients. What’s more, scientists found that the HDLc isolated from CAD patients may actually activate disease-promoting biochemical pathways typical of diseased arteries. Why?
Understanding HDLc Associated Protein, PON1
Armed with these surprising results, the investigators wanted to find out why the HDLc from CAD patients was toxic to arteries. They first examined the HDLc particles purified from serum from both normal and CAD patients. At first, they found little difference in composition. However, upon further examination, the investigators found a dramatic decrease in the activity of an anti-oxidant enzyme, paraoxonase 1 (PON1), in the CAD HDLc, compared to that of a normal subject’s HDLc. Interestingly, in earlier studies this enzyme was also reported to be present at low levels in the serum of CAD patients compared to that of normal healthy subjects. However, the study discussed here was the first to show an important connection between the activity of PON1 and heart disease in humans. PON1 and its possible relationship with heart disease has long flown under the radar, and today few medical professionals even know this enzyme exists.
PON1 and Toxic Oxidants
The results of the above studies indicate that the HDL-bound enzyme PON1 is an important component of HDLc in preventing heart disease. The speculation is that this enzyme protects the endothelial cell by preventing the production of toxic oxidants, such as LDLox, which is produced by inflammatory cells, and found in the atherosclerotic plaques of diseased arteries.
These studies help explain why a CAD patient’s HDLc, which has low levels of PON1 activity, is ineffective in protecting our arteries. It’s simply no match for the disease-producing toxins! Additionally, this may explain why some therapeutic drugs that are effective in raising HDLc in CAD patients may offer little benefit to the patient’s health. Sure the drug increases HDLc, but unfortunately it’s the HDLc with ineffective PON1! However, one HDL-raising therapeutic with positive effects on PON1 activity is niacin, which is often prescribed for patients with unhealthy lipid profiles. Not only does niacin increase HDLc, but it also increases the antioxidant bound to the HDL, PON1.
Interestingly, niacin was the first therapeutic to be prescribed to patients with abnormal blood-lipid levels (high LDLc and triglycerides) more than five decades ago. Niacin remains one of the best therapeutics for maintaining a healthy cardiovascular system.
Promising new research indicates that the nutrients in pomegranates have a stimulatory effect on the activity of the antioxidant enzyme, PON1. Berberine is another potential natural substance shown to help neutralize the toxic oxidants (such as, LDLox) involved in inflammatory reactions in arteries. In a future article, I’ll examine berberine, as well as a fermented yeast product that may help maintain a healthy level of the cholesterol-carrying molecule, LDLc.
At The Heart Of Your Health
Fortunately, there are many simple ways to improve our cardiovascular health that don’t require a prescription, or even a supplement. Topping your cardiovascular must-do list should be regular exercise, followed by a healthy diet rich in fruits and vegetables and stress-management.
Interested in digging deeper into recent scientific research that may impact your cardiovascular health? See Juvenon Health Journal, Volume 8, Number 12,"Cardiovascular Health: How Vitamin B-3 Can Make It Better" and Volume 7, Number 6,"Niacin: A Comeback for the Happy Cholesterol Vitamin."
answers your questions.
question: I’ve never had a heart attack, but recently my physician prescribed a statin drug to lower my cholesterol. However, I stopped taking the drug as it made my muscles ache. Do you have any suggestions as to how I can lower my cholesterol?
Dave - Fort Meyers Beach, Fl
answer: I assume it is your LDL cholesterol that tested at a high level, and this is the reason your doctor prescribed a cholesterol-lowering drug. There are a number of lifestyle changes proven to help reduce LDLc levels, and raise the good cholesterol, HDLc. These changes include regular aerobic exercise and a diet low in sugar and refined grain products such as white bread, pastry and high-glycemic junk foods. Additionally, your diet should be rich in fruits, berries, vegetables and fish. Exercise and a healthy diet may help reduce the LDLc, but it might not be enough to get your LDLc to what is considered a healthy level (<200 mg/dl).
Red yeast rice is natural substitute for the commonly prescribed statin class of cholesterol drugs. Available in vitamin stores, it has been demonstrated to be effective in lowering LDLc. However, small amount of statins may be present in the red yeast rice so it is recommended to have regular check-ups to be sure your liver enzymes are in the normal range. It is also important to consult with your health professional to be on the safe side.
Send your questions to AskBen@juvenon.com.
Dr. Benjamin V. Treadwell is a former Harvard Medical School professor and member of Juvenon’s Scientific Advisory Board.
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A group of investigators from several institutions in Europe and the United States recently pooled their intellectual and technical resources. The team devised an experimental protocol to determine the mechanism(s) involved in the negative effects on the health of arterial endothelial cells from HDLc isolated from patients with coronary artery disease. They were aware of published results that had shocked the cardiology world. These surprising results showed the therapeutic used for raising HDLc in patients with coronary artery disease (CAD), actually produced an unexpected negative effect on their health.
In the experiment reported here, scientists took blood samples from normal, healthy patients and patients with CAD. The HDLc in the blood samples was isolated and purified. The investigators were aware of results from previous studies demonstrating the capacity of HDLc to bind to endothelial cells and to stimulate those cells to produce the vaso-relaxant, nitric oxide. Nitric oxide has a positive impact on the arteries as it acts to relax blood vessels, lower blood pressure, and consequently the stress on arteries, as well as the health of the endothelial cells. The investigators confirmed these early results by repeating this experiment where they added HDLc isolated from the normal patients to human endothelial cells. The obvious next step was to see if a similar effect occurred with the HDLc taken from patients with CAD. The result showed an astonishing lack of effect on nitric oxide production. Additionally, the endothelial cells appeared damaged.
Further analysis of the HDLc isolated from CAD patients revealed a dramatic decrease in the activity of an enzyme normally associated with HDLc , paraoxanase 1 (PON1) as compared to HDLc isolated from normal patients’ serum. PON1 is believed to act as a potent antioxidant. The investigators speculate that in CAD patients’ HDLc, the enzyme (PON1) is inactive, and may be at least partially responsible for the negative effects their particular HDLc has on endothelial cell health.
Additional experiments designed to examine the metabolic pathways associated with the activation of the enzyme, endothelial nitric oxide synthase (eNOS), demonstrated the susceptibility of eNOS to inhibition by cellular oxidants such as malondialdehyde, as well as oxidized LDL. PON1 is crucial because it prevents the formation of these oxidants. The exact mechanism(s) involved in the inactivation of PON1, in CAD patients, is currently under further investigation.
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This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.