George B. Rieveschl Jr. Award for Distinguished Scientific Research:
Engineering Mice To Fight Heart Disease in Humans

This year's Rieveschl Award for Distinguished Scienitific Research honors the work of a researcher whose discoveries concerning the effects of the phospholamban protein on the heart have been a major breakthrough in understanding heart disease.The winner, Litsa G. Kranias, PhD, is a College of Medicine professor and director of cardiovascular biology in the Department of Pharmacology and Cell Biophysics.

The phospholamban (PLB) protein was found to play a major role in the regulation of cardiac contraction and relaxation in mammals. Several years ago, Kranias succeeded in creating a phospholamban knock-out mouse that displayed hyperdynamic cardiac function. Later, she demonstrated the negative effects of phospholamban on heart relaxation by genetically-engineering a mouse that over-expressed PLB and found that this second mouse model demonstrated poor cardiac function. Kranias has also described new pathways concerning the relationships of PLB molecules and the calcium ATPase.

John E. Maggio, PhD, Van Maanen professor and director of the Department of Pharmacology and Cell Biophysics says, "Dr. Kranias continues to make significant research contributions in cardiovascular science." Many internationally-known researchers wrote nomination recommendations for the Rieveschl Award and said that Kranias dominates this field. A University of Illinois at Chicago professor wrote that Kranias' work has gained worldwide recognition and has "provided extensive new information on the cellular biology of the heart muscle."

"Many heart failure problems are caused because the heart cannot relax well enough to fill with blood, says Kranias. Because the presence of PLB impairs heart relaxation, a PLB-inhibiting drug may be a critical breakthrough in the efforts to treat heart disease, which is the leading cause of death in industrialized nations. The intracellular protein phospholamban is named from the Greek words phosphoros and lambano, which together mean to receive phosphate." Specifically, PLB is a small protein found in the sarcoplasmic reticulum of cardiac muscle cells that works to regulate calcium levels in the heart. Calcium is the major ion responsible for heart contraction and relaxation. PLB plays a vital role in calcium regulation, and therefore, the ability of the heart to function properly.

By studying biochemical and physiological changes in phospholamban's effects on calcium, Kranias realized that this protein is particularly important during times of exercise and stress. At these times, PLB no longer inhibits the calcium ATPase enzyme, thereby allowing the heart to relax faster and pump blood more efficiently.

Kranias says, "Our laboratory has been trying to understand the mechanisms underlying heart failure. We design transgenic mice with genetic alterations, which we use as models for studying this devastating condition." Because patients with heart failure possess increased phospholamban activity, mouse models are genetically altered to have either increased or decreased levels of phospholamban present. Mice with lower levels of PLB appear normal, with no differences in blood pressure or heart rate. However, because phospholamban is an inhibitor of cardiac contractility, these PLB-deficient mice have stronger hearts with improved pumping activity.

Conversely, when Kranias and her colleagues developed a mouse with high levels of this inhibitory protein, a situation that resembles the human disease state, they showed a diminished cardiac contractility and a lower pumping activity of the heart. "We are in the process of further characterizing these mouse models with respect to stress, exercise, pharmacological interventions and their responses to various physiological and pathophysiological conditions." Overall, her results show that by controlling the levels or the activity of phospholamban alone in the heart, it is possible to finely tune the heart's pumping action. "Several pharmaceutical companies are now pursuing the development of PLB-inhibitor drugs to reduce its activity. These drugs will potentially be important in the future treatment of heart failure and are expected to have minimal side effects," adds Kranias.

Currently, Kranias' PLB-knockout mouse is used in laboratories around the world to gain an understanding of the most fundamental aspects in the regulation of cardiac performance. The model has been analyzed in numerous biochemical and physiological studies, illustrating how the work initiated by Kranias has helped to provide new information on the cellular biology of heart muscle. One nominator writes about Kranias' research and says, "The fruits of her work could indeed be very far reaching to world health. She epitomizes just the sort of accomplished researcher for whom the award was instituted."

A Canadian researcher writes: "Litsa has always been a very thoughtful and accomplished scientist. In the initial stages of her career, she contributed excellent papers advancing our knowledge of calcium regulation by calcium pumps and PLB in the heart. In the early 1990s, she targeted the PLB gene, knocking it out in a line of mice. In a few papers, she transformed the field in which she worked by demonstrating that PLB is a major regulator of the kinetics of cardiac contractility. These papers have been cited endlessly and she has received recognition and innumerable invitations to talk about her work throughout the world.

These studies were only the beginning, however. Her success in a difficult field put her in a position to lead an offensive aimed at answering more penetrating questions about the regulatory role of PLB and other specific proteins involved in calcium handling. These studies are now in progress with every promise that the results will be as exciting as those achieved through the study of PLB. One of the talents that Litsa has displayed is her ability to harness the enthusiasm of those around her for study of the projects that she has opened to investigation. "I visited her Department a few years ago and was astounded at the collegial way in which she and a group of investigators were sharing their expertise. Past recipients of the Rieveschl Award for Distinguished Scientific Research are those individuals who transformed their various fields. The field in which Litsa works was very different after she published her work."

Another nominator writes: "Litsa is an internationally renowned scientist of great stature, and a leader in the highly competitive field of myocardial calcium handling. She is the recipient of an National Institutes of Health (NIH) Merit Award, and the director of the National Heart, Lung, and Blood Institute, Claude Lenfant, MD, has presented her work to congress as an example of the benefits accrued from increased NIH funding." Kranias says, "Our studies have been extended to the clinical arena, where we model the changes we have observed in human heart failure by creating genetically engineered mice with these same changes. We study cardiac performance in these models, and from these studies, we discover more about the nature of PLB's function in healthy and diseased hearts. Ultimately, our work aims to determine how PLB's inhibition can be relieved in heart failure, which may result in an improved treatment for the disease."