January 26, 2007

Speaker describes ‘clocks’ that pace cardio function

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Garrett FitzGerald, M.D., talks about the molecular ‘clocks’ in the cardiovascular system that seem to run on their own time. (Photo by Susan Urmy)

Speaker describes ‘clocks’ that pace cardio function

The most common time for heart attacks and strokes is early morning, when blood pressure reaches its daily peak.

In humans and other higher animals, a small area in the brain called the suprachiasmatic nucleus is believed to drive the body's daily, or circadian, rhythms. But a few years ago, Garret FitzGerald, M.D., and colleagues found evidence of molecular “clocks” in the cardiovascular system that seem to work on their own, setting the pace for these peripheral tissues.

FitzGerald detailed his group's foray into the field of circadian rhythms at the third annual Grant R. Wilkinson Distinguished Lectureship in Clinical Pharmacology, held last week.

FitzGerald, currently a professor of Medicine and the Elmer Bobst Professor of Pharmacology and Therapeutics at the University of Pennsylvania School of Medicine, spent several years at Vanderbilt University Medical Center — arriving in 1980 as a fellow, and later serving as the director of the Division of Clinical Pharmacology.

Well known for his work on cyclooxygenase (COX) enzymes, FitzGerald's work contributed to the adoption of cardioprotective low-dose aspirin therapy. He was also the first to predict the risk of cardiovascular events with COX-2 inhibitors like Vioxx and Celebrex.

Since moving to Penn, his group has identified a protein, which they called MOP4, that appeared to work in conjunction with BMAL1 — one of the key “clock” proteins in the brain — to activate gene expression. Additionally, they've noted a role for retinoic acid receptors, a type of hormone receptor that recognizes derivatives of vitamin A, in regulating MOP4's activity.

“We provided the first evidence for how a hormone can signal to a clock in the periphery,” said FitzGerald, also the chair of the Department of Pharmacology and director of the Institute for Translational Medicine at Penn.

FitzGerald's ongoing research aims to address how such peripheral clocks communicate with the master clock in the suprachiasmatic nucleus.

The endowed Wilkinson lectureship was established in 2005 to honor the contributions of the late Grant R. Wilkinson, Ph.D., D.Sc., widely known for his contributions to understanding why patients vary in their response to drugs. Wilkinson, whose papers are among the most frequently cited by pharmacologists worldwide, was a professor of Clinical Pharmacology at VUMC from 1971 until his death last year.

Private and corporate sponsors, including many of Wilkinson's colleagues at Vanderbilt and around the world, contributed to the endowment, which supports an annual lecture by a world-class authority in Clinical Pharmacology, drug metabolism, pharmacokinetics or pharmacogenetics.