Testing of anti‐atherogenic drugs on cell cultures: reliability questioned

Abstract

In the series of publications, started in 1986 by E.I. Chazov et al. (The Lancet, 2:595) and continued until today by A.N. Orekhov until today, was reported that culturing of smooth muscle cells with the serum from patients with cardiac atherosclerosis caused lipid infiltration of the cultured cells, while serum from healthy individuals had no such effect. Cell cultures were used for testing of drugs and food components for the purpose of their official registration. Numerous substances have been reported anti‐atherogenic: statins, trapidil, prostaglandin E2, dibutyryl cyclic AMP, calcium antagonists, lipoxygenase inhibitors, carbacyclin, extracts of different mushrooms species, quid liver, krill meat, derivatives of garlic, black elder berries, calendula, violet flowers, hop cones, grape seeds etc. On the contrary, beta‐blockers, phenothiazines, oral hypoglycemics etc. were reported pro‐atherogenic. Clinical recommendations were formulated including exact dosage of drugs. It is known, however, that anti‐atherogenic or lipid‐lowering agents can influence cholesterol synthesis, lipid metabolism in the liver or endothelium‐related mechanisms. All these targets are absent in cell cultures. In vivo, relationship between cholesterol uptake by cells and atherogenesis is inverse rather than direct: in familial hypercholesterolemia caused by abnormality of cellular LDL‐receptors, which are present also on the smooth muscle cells, inefficient clearance of LDL causes hypercholesterolemia and predisposition to atherosclerosis. Accordingly, if a pharmacological agent reduces cellular cholesterol uptake in vitro, it should be expected to cause cholesterol elevation in vivo. Unreliability of results and conclusions can be proven by reductio ad absurdum: pharmacological agents which are “anti‐atherogenic” in cell cultures must be pro‐atherogenic in vivo.