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Matters of the Heart

Matters of the Heart
Basic research finding answers to cardiovascular enigmas

December 2002

by Will Sansom

Imagine you are a young cell, nicknamed Stem, and you are about to graduate from Cellular City High School. You are one of the top students, and Liver University, Heart Tech and other top-notch cellular colleges have their eyes on you. Where do you choose to go?

Stem Cell is fictitious, of course, but he helps us understand a normal process in our bodies: cell differentiation, by which an undefined (or stem) cell becomes a cell with a specific physiologic purpose.

Basic research of cardiovascular disease at the Health Science Center covers many diverse topics. This article features the work of two laboratories. One conducts studies of cell differentiation with an eye toward understanding how stem cells become heart muscle cells. The other asks why some women develop high blood pressure after menopause and others do not.

Anthony B. Firulli, Ph.D., assistant professor of physiology, seeks to discover which molecules are the movers and shakers in influencing cells to become cardiomyocytes (heart muscle cells). "A cell is a blank slate when it starts out," he said. "As development ensues, cells make decisions that exclude them from making other decisions. They walk through a one-way door to their destiny." Understanding of this process could lead to preventive treatments for holes in the heart wall and other congenital defects. One in 1,000 live births involves a cardiac defect, making it the most prevalent congenital defect in the human population.

A barrage of signals from growth factors and other hormones influence a cellís decisions. Ultimately, the genetic instructions that guide the cellís activities are programmed. DNA, the genetic blueprint in every cell, is a code containing many sets of instructions. "Entities called transcription factors do what their name suggests Ė they transcribe from the DNA code the correct instructions as to what the cell should be," Dr. Firulli said. "We study two transcription factors that are tied to the development of cardiomyocytes. These factors implement the expression of genes specific for cardiac cell lineage, and our goal is to deduce the mechanisms involved in this regulation."

Defining the molecular pathways that orchestrate cardiac development could provide clues to managing adult heart disease, as well. "A hierarchy of genes is expressed in the fetus," Dr. Firulli said. "These genes help form the heart and take care of embryonic needs in the womb. In the adult, with the onset of heart disease, there is a re-expression of these genes. The physiologic demands on the heart are based on an increase in pressure. The heart reacts by turning on these early genes, which causes existing cells to grow in mass. This thickens the heart wall, protecting the heart from the increase in pressure.

"Unfortunately, the effects of this change in gene expression are harmful over time. We are studying genes that are involved in this response, with the goal of using this information to manage cardiovascular disease."

Grants from the National Heart, Lung, and Blood Institute and the March of Dimes support Dr. Firulliís research. He is a member of two American Heart Association study sections that review grant proposals, and is a previous AHA grant recipient.

Carmen Hinojosa-Laborde, Ph.D., associate professor of pharmacology, asks a very different question: Why do some women develop post-menopausal high blood pressure, or hypertension, while others do not? Salt-sensitive blood pressure and the hormone estrogen seem to play prominent roles. Dr. Hinojosa-Labordeís laboratory studies a rodent model of salt-sensitive blood pressure. These animals, like many humans, have normal blood pressure when they eat a low-salt diet, but become hypertensive if they eat a high-salt diet.

"I have shown that removing the estrogen by removing the ovaries from these animals will result in salt-sensitive hypertension," she said. "When the estrogen is replaced, the hypertension does not develop." She is investigating the contributions of two major controllers of blood pressure, the sympathetic nervous system and the renin-angiotensin system, in the development of post-menopausal hypertension.

In a three-month experiment, Dr. Hinojosa-Laborde studied three groups of salt-sensitive rodents Ė one group with the ovaries removed to mimic menopause, one group with the ovaries removed but receiving estrogen replacement, and a control group with intact ovaries. In this study, the salt-sensitive rodents with no estrogen became hypertensive before the other animals. The researchers measured blood pressure by the reading of radio signals. They placed a small transmitter inside an artery, and the transmitter emitted a radio signal to a receiver outside the cage. "We had 24-hour recordings of blood pressure for a period of three months," Dr. Hinojosa-Laborde said.

In a second study, the researchers followed the three groups of animals for a year. "We observed that when the salt-sensitive animals reached middle age, they developed hypertension," Dr. Hinojosa-Laborde said. "The animals with no estrogen became hypertensive more quickly, and those with estrogen replacement were protected against the hypertension." She presented the data last September in Orlando, Fla., at the meeting of the American Heart Associationís Council for High Blood Pressure Research.

These are but a couple of the many intriguing cardiovascular research projects under way at the Health Science Center. The goal is better heart health for us all.

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