Plenary Lecture

Plenary Lecture

Activation of Genes in Atheroprotection, Regression of Atherosclerosis and Longevity

Professor Pauli V. Luoma
Institute of Biomedicine, Pharmacology
P. O. Box 63, FIN-00014 University of Helsinki

Coronary heart disease (CHD) has been recognised as the leading cause of death in the world and cerebrovascular disease as the second leading cause. The liver is the principal site for the synthesis of lipids and proteins, and alterations in hepatic function influence plasma lipoprotein levels. This lecture focuses on the effects of gene activation on the atherosclerotic vascular process and the occurrence of atherosclerotic disease.
Our studies originating in the 1970s linked drug-caused gene activation and high protein, phospholipid and cytochrome P450 concentrations in the liver with high apolipoprotein AI and HDL cholesterol and reduced LDL cholesterol levels in plasma and presented the view that gene-activators have exploitable effects against atherosclerosis. Investigations performed in following years have shown that P450-enzymes respond to excess cholesterol and act in maintaining cholesterol homeostasis and that gene-activators act against the atherosclerotic process. The compounds include drugs indicated for lipid disorders such as statins, fibrates, niacin and cholestyramine, as well as compounds for other purposes. Gene-activators generate signalling mediators such as oxysterols and eicosanoids and, via nuclear receptors, upregulate apolipoprotein AI, ABCA1 and other transporters that efflux cell cholesterol, transport it to the liver and eliminate it into bile, and prevent cholesterol absorption in the intestine. P450-derived eicosanoids and their metabolites have vasodilatating effects and inhibit inflammatory response. A number of gene-activating agents including statins, niacin, cholestyramine, calcium channel blockers, angiotensin receptor blockers and pioglitazone regress atherosclerosis in coronary and / or carotid arteries. Several of them reduce the occurrence of fatal and /or non-fatal CHD and cerebrovascular disease, and also all-cause mortality, and enhance longevity. Investigational gene-activators include LXR, PPAR and PXR agonists and other compounds with potential as antiatherogenic agents.

Brief Biography of the Speaker:
Pauli Luoma graduated from the University of Oulu Medical School, Finland in 1967. In the 1960s he worked as a general practitioner in Municipial Health Service in Northern Finland and as a research associate in the Department of Pharmacology, University of Oulu. He specialized in internal medicine and clinical pharmacology, and worked as postdoctoral fellow in Virginia Commonwealth University (1975-1976) and research fellow of the Academy of Finland (1976-1979). In the 1980s he practitioned as senior specialist in the Department of Internal Medicine, University Hospital in Oulu, and in the 1990s in Municipial Health Service and as internist in Central Hospitals in Northern Finland. He is docent in clinical pharmacology at the University of Tampere Medical School, Finland (1981), and docent in internal medicine, University of Oulu (1982), and professor (2000). His research interests, now in the Bioinstitute of Medicine, Department of Pharmacology, University of Helsinki, focus on liver function and gene activation, and particularly on cytochrome P450, lipids, proteins and transporters acting in processes that regress atherosclerosis and reduce the occurrence of atherosclerotic disease. He is author of about 70 papers published in international journals and conference proceedings, and invited book chapters.



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