Department of Medicine

theHeart.org | US researchers have pinpointed a genetic factor that affects diseases of both the heart and blood vessels and identified a molecular pathway shared between the two. They propose that a subset of human heart and vascular disease may be due to deficiency of this genetic factor, known as Krüppel-like factor 15 (Klf15), and that amending the pathway in some way could help ameliorate both diseases.

Dr Saptarsi M Haldar (Case Western Reserve University, Cleveland, OH) and colleagues report their findings online April 7, 2010 in Science Translational Medicine.

“Often, people think of cardiac disease and vascular disease as separate entities, but they often run together—for example, in Marfan’s syndrome or in aging, when there are degenerative changes to both the heart and blood vessels,” senior author Dr Mukesh K Jain (Case Western Reserve University) explained to heartwire.

Some years ago, his research team identified the genetic factor Klf15 and showed that it was expressed in both the heart and aorta; they also demonstrated that in human tissue from patients with heart failure or aortic aneurysmal disease, the expression of Klf15 was markedly reduced. The new research is an attempt to identify a common molecular pathway for these effects that could represent a potential therapeutic target.

Both heart and blood vessels affected by Klf15 deficiency

“We hypothesized that maybe the absence of Klf15 or its relative deficiency might be unhealthy, so we generated mice to mimic this,” Jain explains. The mice, which were completely deficient in Klf15, were then stressed using angiotensin 2, and they developed heart failure and, “quite unusually,” aneurysms at the same time, he notes, “so we showed that both the heart and blood vessels of the mice were affected by deficiency of Klf15.

“We then wondered whether there was a common molecular mechanism that might explain this shared pathology,” he continued.

They went on to show that enhancement of the activity of p53—a protein most often associated with protection against cancer—appeared to be causing the adverse effects in the setting of Klf15 deficiency.

Furthermore, they showed that Klf15 functions as a “molecular brake” on p53 function by inhibiting p53 acetylation, which is a critical “on” switch for this protein.

These molecular effects were operative both in the Klf15-deficient mice and in human tissues from heart-failure patients, which were also found to be Klf15 deficient.

Boosting Klf15 production or blocking p53 acetylation may be of benefit

“This now lends us the opportunity to try to identify a chemical compound that might either boost the activity of Klf15 or somehow block the acetylation of p53, which might help ameliorate diseases affecting both the heart and blood vessels,” Jain noted. As well as aging and Marfan’s syndrome, this includes peripartum cardiomyopathy and in particular a subset of women who develop aortic dilatation as well as heart failure in the setting of pregnancy, he explained.

The discovery of new molecular pathways that are amenable to therapeutic manipulation is of immense clinical value,” he says, adding that research into compounds targeting Klf15 or p53 is already under way. Researchers have already demonstrated that a compound called curcumin, the active constituent of the spice turmeric that is often used in Asian cooking, is able to block the acetylation of p53, and they are actively trying to identify other compounds that could enhance the expression of Klf15.

Read the abstract on CWRUmedicine.org