VCU Researcher Receives NIH MERIT Award for Research in Heart Protection

By Sathya Achia Abraham

A Virginia Commonwealth University researcher who has been studying how male impotence drugs can help protect or minimize muscle damage following a heart attack has received a MERIT award from The National Institutes of Health’s National Heart, Lung and Blood Institute totaling nearly $4 million.

Rakesh C. Kukreja, Ph.D., professor of internal medicine and the Eric Lipman professor in cardiology in the VCU School of Medicine, more than 15 years ago began to explore “preconditioning,” a way to protect the heart muscle from serious damage in the future by subjecting it to very brief periods of deprivation of blood flow and, therefore, oxygen.

Through basic research, Kukreja has harnessed an understanding of the mechanisms by which heart cells die due to lack of oxygen, and has identified some of the biochemical and molecular signaling pathways involved in preconditioning.

This preconditioning effect was modeled in his lab by “pretreating” animals with male impotence drugs known as phosphodiesterase-5 inhibitors (PDE-5) for heart protection. PDE-5 is an enzyme responsible for the destruction of cGMP, an intracellular messenger molecule, in heart cells. PDE-5 inhibitor drugs are able to preserve cGMP, and therefore dilation of the arteries by inhibiting PDE-5.

Kukreja has shown that Viagra®, generically known as sildenafil, induces a cardioprotective effect that is almost equivalent to that induced by preconditioning. Sildenafil preconditions by increasing the desirable levels of nitric oxide and opening the mitochondrial KATP channels. A preconditioned or pretreated heart has an improved ability to produce nitric oxide and may directly improve a patient’s outcome following a heart attack. Generally, damage following a heart attack is related to an inability to recover from lack of oxygen.

Recently Kukreja and his colleagues published findings on another PDE-5 inhibitor, Levitra®, generically known as vardenafil, which like sildenafil, stabilizes the mitochondria and protects against damage of the heart by opening the mitochondrial KATP channels in cardiac cells. Mitochondria are cellular organelles critical for converting oxygen into ATP, the key fuel for cellular function.

Kukreja and his colleagues have also demonstrated that sildenafil prevented damage to the heart from doxorubicin, a potent chemotherapeutic agent frequently used in the treatment of breast cancer, leukemia and sarcomas. The research also showed that the impotence drug prevented dilated cardiomyopathy and heart failure in doxorubicin treated mice.

Kukreja’s work on the powerful cardioprotective effects of PDE-5 inhibitors has great clinical potential as this drug is widely used in patients who have coronary artery disease. He said that the PDE-5 inhibitors may be developed for future use to protect the brain, liver and other organs against ischemic injury – those injuries that are caused by lack of oxygen.

The NIH’s MERIT award, or Method to Extend Research in Time, program is highly selective and is given to investigators who have demonstrated superior competence and productivity during previous research projects. Furthermore, the program provides top researchers more time to focus on research without the administrative burdens of preparing and submitting applications for a research extension. The four or five year extensions may be granted to the top 1 to 2 percent of grants.

Kukreja has published more than 110 articles in peer-reviewed journals and has served as an editorial board member on several cardiovascular journals, including the American Journal of Physiology (Heart & Circulatory Physiology), Circulation
Research, Molecular and Cellular Biochemistry, and the Journal of Molecular and Cellular Cardiology.