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New target for heart failure therapy identified

September 25, 2015

The findings, which will be published online this week in Proceedings of the National Academy of Sciences, show that aldosterone production is mediated by a protein called beta-arrestin-1. Beta-arrestin-1 binds to angiotensin II receptors when they are activated by angiotensin II.

Aldosterone is secreted by the adrenal cortex. Its levels are elevated in chronic heart failure, and its presence contributes to morbidity and mortality of the disease. It contributes to heart failure progression and diminished cardiac function after myocardial infarction.

The production of aldosterone was previously thought to be solely the result of the activation of G-proteins, which are also activated when angiotensin II binds to its receptors, according to Anastasios Lymperopoulos, Ph.D., a Post-Doctoral Research Fellow in the Center for Translational Medicine and the George Zallie and Family Laboratory for Cardiovascular Gene Therapy at Jefferson Medical College of Thomas Jefferson University.

"The bottom line is that in order to effectively suppress aldosterone production, you need to inhibit beta-arrestin-1 in addition to inhibiting G-proteins," said Dr. Lymperopoulos, who is the lead author of the study.

All the drugs currently available for suppression of aldosterone by angiotensin II primarily target G-protein signaling pathways. However, Walter Koch, Ph.D., the W.W. Smith Professor of Medicine and the Director of the Center for Translational Medicine and the George Zallie and Family Laboratory for Cardiovascular Gene Therapy, said that these data clearly show that beta-arrestin1 plays a more significant role in aldosterone secretion than G-proteins.

"Aldosterone secretion is dependent on beta-arrestin-1," Dr. Koch said. "It may not be independent of G-proteins, but beta-arrestin-1 is definitely the critical player. The goal should be to find a new antagonist that can block beta-arrestin-1 and G-protein activation equally well. Doing so would lead to lower aldosterone levels at its source and alleviate negative remodeling processes in the injured heart."

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Researcher Dr Tom Barber said:

"Polycystic ovary syndrome is an incredibly common condition affecting 1 in 10 women of reproductive age and is a leading cause of infertility. It is a genetic condition and one that is strongly associated with obesity; it is therefore of huge relevance for women given today's obesity epidemic. Our research shows that a variant of the FTO gene that has previously been shown to be associated with obesity also influences susceptibility to polycystic ovary syndrome. These data provide the first genetic evidence to corroborate the well documented association between these two conditions. Our future work will focus on elucidating the underlying mechanisms of polycystic ovary syndrome and its metabolic consequences with the hope of understanding how this common condition develops. This in turn will instruct future therapeutic developments for women who suffer from polycystic ovary syndrome."

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