FEATURE ARTICLE
Statins: From Fungus to Pharma
The curiosity of biochemists, mixed with some obvious economic incentives, created a family of powerful cardiovascular drugs
Philip A. Rea
Clearing the Way
According to the World Health Organization, cardiovascular diseases are the leading cause of death. In 2005, for example, about 17.5 million people died from these diseases, accounting for about 30 percent of global mortality.
Just a few years ago, general practitioners, and even many cardiologists, would have labeled cardiovascular disease as a straightforward plumbing problem: Fat-laden gunk on the surface of artery walls blocks the flow of blood. If the tissue downstream of the blockage is cardiac muscle, a heart attack results; if it's brain tissue, a stroke ensues. We now know that there is a lot more to it than this.
The modern understanding of cardiovascular disease started to emerge in 1961, when the first reports from the Framingham Heart Study were published. This project examined 5,209 men and women, ages 30-62, who lived in Framingham, Massachusetts, a small, predominantly middle-class town just outside of Boston. The results revealed that high blood pressure, smoking and high levels of blood cholesterol are all bad for your heart. In particular, this study showed that there is a tight correlation between blood-cholesterol levels and the likelihood of later developing cardiovascular disease.
Pivotal as these findings were, they were only the prologue to a story that was to prove more complex.
First, cholesterol is not all bad news. This lipid makes up a crucial component of biological membranes and serves as a precursor for other necessary substances, including the sex hormones estrogen and testosterone. Indeed, because of its necessity cholesterol does not come exclusively from dietary sources but is also manufactured by the liver and to a lesser extent by a few other tissues, including the intestine.
Second, it is not cholesterol in general that is the problem, but rather the form it is in that matters. Atherosclerosis ("hardening of the arteries") arises from the low-density lipoprotein (LDL) form of cholesterol. These LDLs—globules of about 20 nanometers or so across—encapsulate cholesterol derivatives called cholesteryl esters.
When the bloodstream contains a surplus of LDLs, they enter the innermost layer of cells of the arterial wall and accumulate. Eventually, these lipids oxidize, which triggers metabolic and structural changes in the arterial wall, not unlike those elicited by infection from a pathogen. The immune system identifies these changes as damage, driving the formation of capped plaques replete with fat-engorged white blood cells. It is when these plaques are disrupted that trouble arises: Blood leaks through the fissure into the lipid-rich core of the structure to make contact with proteins that promote coagulation, resulting in clots. That is the downside.
The upside of cholesterol comes from the high-density lipoprotein (HDL) form, which, unlike its LDL counterpart, is cardioprotective. HDLs—globules only 8-11 nanometers across—pick up cholesterol from the blood and prevent or impede plaque progression by retrieving arterial cholesterol deposits and limiting the rate and extent of LDL oxidation. Higher levels of HDLs thereby reduce the risk of cardiovascular disease. Of course, that is not to say that there can never be too much of a good thing: Some studies indicate that very high levels of HDLs also increase the risk of cardiovascular diseases.
Third, cholesterol tightly regulates its own production. A seminal finding in the science of cholesterol came in 1966 when Marvin D. Siperstein and Violet M. Fagan—both then at the University of Texas Southwestern Medical School—showed how the body controls cholesterol levels. These investigators discovered that the enzyme that converts a substance named HMG-CoA to mevalonic acid, the immediate precursor of cholesterol, is inhibited by cholesterol. By feedback inhibiting the pacemaker enzyme that catalyzes the first committed and rate-limiting step in the pathway, cholesterol downregulates its own synthesis.
A major culprit in heart disease—cholesterol—and a potential therapeutic target—the enzyme HMG-CoA reductase—had been discovered.
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