cardiovascular medicine publications :: Q2 | 2010

Treatment of Pericardial Disease
Azam S, Hoit BD.
Cardiovasc Ther. 2010 Apr

Kruppel-like factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression
Yori JL, Johnson E, Zhou G, Jain MK, Keri RA.
J Biol Chem. 2010 May

Kruppellike Factor 15 Regulates Smooth Muscle Response to Vascular Injury
Lu Y, Haldar S, Croce K, Wang Y, Sakuma M, Morooka T, Wang B, Jeyaraj D, Gray SJ, Simon DI, Jain MK.
Arterioscler Thromb Vasc Biol. 2010 May

Krüppel-like factor 4 regulates pressure-induced cardiac hypertrophy
Liao X, Haldar SM, Lu Y, Jeyaraj D, Paruchuri K, Nahori M, Cui Y, Kaestner KH, Jain MK.
J Mol Cell Cardiol. 2010 Aug

Klf15 deficiency is a molecular link between heart failure and aortic aneurysm formation
Haldar SM, Lu Y, Jeyaraj D, Kawanami D, Cui Y, Eapen SJ, Hao C, Li Y, Doughman YQ, Watanabe M, Shimizu K, Kuivaniemi H, Sadoshima J, Margulies KB, Cappola TP, Jain MK.
Sci Transl Med. 2010 Apr

Fatty acid-binding protein 5 and PPARbeta/delta are critical mediators of epidermal growth factor receptor-induced carcinoma cell growth
Kannan-Thulasiraman P, Seachrist D, Mahabeleshwar G, Jain MK, Noy N.
J Biol Chem. 2010 Jun

Cardiac rehabilitation in heart failure: a brief review and recommendations
Piña IL.
Curr Cardiol Rep. 2010 May

Impact of ICD battery longevity on need for device replacements-insights from a Veterans Affairs database
Ramachandra I.
Pacing Clin Electrophysiol. 2010 Mar

Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner
Han Y, Kuang SZ, Gomer A, Ramirez-Bergeron DL.
Stem Cells. 2010 Apr

The intrinsic complement regulator decay-accelerating factor modulates the biological response to vascular injury
Sakuma M, Morooka T, Wang Y, Shi C, Croce K, Gao H, Strainic M, Medof ME, Simon DI.
Arterioscler Thromb Vasc Biol. 2010 Jun

Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials
Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC.
Lancet Oncol. 2010 Jun

Vanoxerine, a new drug for terminating atrial fibrillation and flutter
Matsumoto N, Khrestian CM, Ryu K, Lacerda AE, Brown AM, Waldo AL.
J Cardiovasc Electrophysiol. 2010 Mar

[(Methyl)1-(11)C]-Acetate Metabolism in Hepatocellular Carcinoma
Salem N, Kuang Y, Corn D, Erokwu B, Kolthammer JA, Tian H, Wu C, Wang F, Wang Y, Lee Z.
Mol Imaging Biol. 2010 Apr

In situ fluorescence imaging of myelination
Wang C, Popescu DC, Wu C, Zhu J, Macklin W, Wang Y.
J Histochem Cytochem. 2010 Jul

theHeart.org feature CWRUmedicine research on shared molecular pathway identified for cardiac and vascular disease

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