title: Gene-activators prevent and regress atherosclerosis and reduce mortality.
abstract: Atherosclerotic cardiovascular disease is a major health problem worldwide. This article reviews studies clarifying the effects of gene-activating agents on the atherosclerotic vascular process, the occurrence of fatal and nonfatal atherosclerotic disease, and all-cause mortality. Studies originating in the 1970s linked drug-caused gene induction and high protein and cytochrome P450 concentrations in the liver with high apolipoprotein AI (apo AI) and HDL cholesterol (HDL-C) and reduced LDL cholesterol (LDL-C) levels in plasma and presented the view that the inducers, gene-activators, have beneficial exploitable effects against atherosclerosis. The following studies have shown that P450-enzymes respond to cholesterol accumulation and act in maintaining cholesterol homeostasis and that gene-activators act against the atherosclerotic process. The compounds include drugs indicated for dyslipidemias, such as statins, fibrates, niacin and cholestyramine, as well as compounds used for other purposes, including calcium channel blockers, angiotensin receptor blockers and glitazones. The compounds generate signaling mediators such as oxysterols and eicosanoids. The gene-activators upregulate, via the activation of nuclear receptors, genes encoding proteins such as apo AI and ATP-binding cassette (ABC) A1 transporters that efflux cellular cholesterol, transport it to the liver and excrete it into bile, and prevent cholesterol absorption in the intestine. Several statins, niacin, cholestyramine, calcium channel blockers, angiotensin receptor blockers, pioglitazone and etidronate regress atherosclerosis in coronary and /or carotid arteries. Other compounds, including fibrates, phenobarbital and alcohol also have positive antiatherogenic effects. Several gene-activators reduce mortality and / or morbidity from coronary heart disease and cerebrovascular disease, and also death from any cause.
authors.affiliation: Institute of Biomedicine, Pharmacology, FIN-00014 University of Helsinki, Finland. eeva.harju@helsinki.fi
authors.forename: Pauli V
authors.initials: PV
authors.lastname: Luoma
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality* / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002373:Cyclic AMP Receptor Protein / Q000494:pharmacology* / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D002373:Cyclic AMP Receptor Protein; D045162:Thiazolidinediones; D003577:Cytochrome P-450 Enzyme System