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University of Toronto researchers get to the heart of heart failure

University of Toronto

Researchers at the University of Toronto and the University Health Network have identified two genes that play critical roles in heart function - one that contributes to heart failure and one that protects against it.

"This finding is really amazing because it opens up new avenues for the treatment of cardiovascular diseases and heart failure," says Professor Josef Penninger of U of T's medical biophysics and immunology departments and lead author of a study in the June 20 issue of Nature. He and colleague Dr. Peter Backx, a physiology and medicine professor at U of T's Heart & Stroke/Richard Lewar Centre, found that when both genes - angiotensin converting enzyme (ACE) 1 and 2 - are in balance in mice models, the animals developed healthy hearts.

The researchers initially began the study by looking for genes that controlled heart development in flies. Intrigued by finding that the fly's ACE 2 gene is essential in the development of fly hearts, they broadened the study and look for the role of ACE 2 in rats that develop hypertension and cardiovascular disease.

Using genetically-engineered mice, the researchers found that mice carrying the ACE 1 but not ACE 2 gene developed cardiovascular disease and impaired heart function. It is known that ACE 1 serves an important cardiovascular function by generating certain hormones that cause blood vessels to constrict, which helps the body maintain proper blood pressure. The new study by the Toronto team, however, offers a completely new concept for heart function. ACE 1 by-products may regulate blood pressure and control heart function, but if unchecked, they also can contribute to the progression of heart disease, coronary artery disease and heart failure.

"This is the first time that scientists have been able to show that the ACE 1 enzyme is a critical contributor to the inability of the heart to function optimally. Perhaps even more important, we've also shown that the ACE 2 gene plays a highly protective role in heart function by counteracting the negative effects of ACE 1 by-products," says Penninger.

ACE 2 appears to produce its beneficial effects on the heart by preventing the actions of peptide hormones generated by ACE 1, says Backx, a heart disease specialist. "This research solidifies the view that the protective effects of ACE 1 inhibitors (drugs now commonly prescribed for patients with hypertension, cardiovascular disease and coronary heart disease) work by directly interfering with the production of these peptide hormones generated by ACE 1 enzymes. Up to now, nobody knew how this system worked."

Unfortunately, while ACE 1 inhibitors do help slow the progression of heart disease, they are not always effective and their current use is often limited by side effects, Backx says. "But if we understand the connection between peptides and ACE inhibitors, we can begin to tailor the drugs to be much more specific."

The researchers say the study establishes the fact that ACE 2 plays a fundamental role in the cardiovascular system of rats, mice and flies, which strongly suggests the gene is also an important regulator of cardiovascular function in humans. "What I found interesting is that the hearts in our mice looked like human ones with coronary heart disease," says Penninger. "The transgenic mouse models created in these studies can now be used to develop new approaches to heart disease therapy and new approaches for genetic screening if people are at risk for heart disease and heart failure."

Hypertension is a disease that afflicts over 25 per cent of the population aged 45 and older. Left unchecked, it leads to heart attacks, stroke, coronary artery disease and heart failure. Collectively, cardiovascular disease is now recognized as the major cause of death and disease in modern societies. Despite recent predictions that death from cardiovascular disease will be the world's number one killer within the next 10 years, the genetics and mechanisms of heart disease are poorly understood.

The study was performed at the University Health Network by Michael Crackower, a post-doctoral fellow in Penninger's lab, and at U of T by Gavin Oudit, a clinician scientist in Brackx's lab. The lead researchers also received assistance from U of T researchers Armen Manoukian and York Pei, Chana Yagil and Yoram Yagil of Ben-Gurion University in Israel and Mark Chappell and Carlos Ferrario of Wake Forest University in North Carolina.

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This research was supported by AMGEN Inc., the Institute for Molecular Biotechnology of the Austrian Academy of Sciences, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation of Ontario.

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