In a study in the current issue of Circulation, researchers in the laboratory of Dr. Antony Rodriguez, assistant professor of molecular and human genetics at BCM, describe the role of a tiny genetic molecule, known as microRNA-22, or miR-22. This molecule’s role sheds light on a molecular mechanism that predisposes the heart to heart failure during prolonged stress.
Influence of miR-22 on genetic expression, heart function
Rodriguez, along with postdoctoral fellow and first author on the study Dr. Priyatansh Gurha, determined that at specific times during stress, miR-22 acts to shutdown key genes by binding to their mRNAs to ensure the heart operates normally. Researchers then removed miR-22 from mice and monitored cardiac physical and morphological changes as compared with mice with an intact miR-22 gene in controlled experiments.
In a twist, hearts of mice without miR-22 became enlarged, weakened and unable to pump blood efficiently after stress. By contrast, hearts of mice with an intact miR-22 responded normally to stress.
A key finding in this study revealed that miR-22 normally optimizes the expression of a number of genes involved in meeting energy needs of the heart.
However, in mice without miR-22, the heart was unable to maintain expression of these genes which then contributed to early exhaustion of the heart.
“Absence of miR-22 also caused decreased expression of many genes implicated in heart disease, including MYH6, MYH7, TITIN, and SERCA2. These genes are essential for cardiac contractility and normal operation of the heart,” said Gurha. “Our studies suggest miR-22 normally assists the heart by maintaining expression of these genes during times of stress.”
Congestive heart failure
Cardiac decomposition, or congestive heart failure, is a serious medical condition characterized by an inability of the heart to pump enough blood and it is estimated that each year more than 250,000 Americans die from related complications.
Implications of these findings
“If you think about it, the heart is a remarkable organ which is able to adapt to a variety of stressful conditions to deliver oxygen every second of your life. However, pathologic stress for long periods of time can lead to a failing heart and eventually death,” said Rodriguez. “An understanding of how the heart copes with pathologic stress could someday help in the treatment, prevention and diagnosis of heart failure. “This breakthrough may help researchers to untangle the genetic basis of heart failure and lead the way to potential therapies.”
Rodriguez said the next step in his research will be to understand how miR-22 regulates energy and metabolic needs of the heart at times of stress.
“In the future, we would also like to know if increasing the dosage of miR-22 might prove effective in prevention of heart failure in experimental models,” he said.
Others who contributed to the study include Maricela O. Ramirez, Ana L. Drumond, Yuqing Chen, Brendon Lee, Tiannan Wang, Xander H. Wehrens, Mark L. Entman, Anilkumar K. Reddy and George E. Taffet, all of Baylor College of Medicine; Cei Abreu-Goodger, Stijn van Dongen, Nenad Bartonicek and Anton J. Enright of the EMBL- European Bioinformatics Institute, Wellcome Trust Genome Campus, Hixton, Cambridge, UK; Robert J. Kelm Jr. with the University of Vermont College of Medicine; and Allan Bradley with the Wellcome Trust Sanger Institute, Genome Campus, Hixton, Cambridge, UK.
This research was supported through funding from the American Heart Association-National Scientist Development Award and Gillson-Longenbaugh Foundation Award.