New knowledge starts here
A foe so formidable as cardiovascular disease (CVD) has to be attacked on many fronts, which is exactly what the physicians and scientists at Pauley Heart Center are doing. In basic science labs and clinical labs, across subspecialties and disciplines, our research teams are working to discover new knowledge that will prevent CVD and improve care for CVD patients. Heart center scientist Dr. Rakesh Kukreja and his colleagues are focusing their research efforts on novel strategies for protecting the heart from injury associated with cardiac ischemia.
"The major cause of cardiovascular disease involves ischemia, which is basically the inefficient delivery of oxygen to the cells of the heart, mainly the heart muscle cells or cardiomyocytes," Kukreja said. "These cells, after a period of stress, begin dying and the efficiency of the heart's pumping action declines. Additional damage can occur with reperfusion, which is when blood supply returns to the tissue after a period of ischemia, for instance, after a heart attack."
"Our lab is studying pharmacological and physiological tools that precondition the heart, making it more resistant to ischemic attacks, and therefore reducing or eliminating the damage from heart attack."
The value of Kukreja's research is evidenced in his funding history, as well as in his designation as a National Institutes of Health MERIT investigator, which is an award given to outstanding scientists who are conducting research of importance to NIH. He has been continuously funded since 1989 by NIH and currently has funding in excess of $6 million for his research projects.
Kukreja's research quality and productivity was instrumental in VCU recently being awarded a $5 million grant from the NIH National Center for Research Resources for renovation of a state-of-the-art cardiovascular research center. The new facility will provide necessary infrastructure to support greater depth and breath of cardiovascular injury and repair research. Kukreja's first major breakthrough came in 2002, when he and his colleagues discovered that the most popular erectile dysfunction (ED) drug, sildenafil (Viagra) induced a powerful protective effect against myocardial damage after experimental heart attack in animal models. Based on those extraordinary results, his lab has continued to expand the concept of cardioprotection with ED drugs, including tadalafil (Cialis) and vardenafil (Levitra) in ischemia/reperfusion injury, heart failure and cardiomyopathy caused by myocardial infarction. The lab has continued to generate important new discoveries, including the following:
- Demonstrated, for the first time, that sildenafil (Viagra) directly protects adult cardiomyoctyes against necrosis and apoptosis following ischemia-reoxygenation injury. Sildenafil caused significant preservation of mitochondrial membrane potential that is essential for production of ATP and cellular homeostasis.
- These results suggest that vasodilatation caused by sildenafil or the presence of other cell types may not be a prerequisite for the potent protective effect of this drug. Sildenafil also induced early up-regulation of Bcl-2/Bax ratio, which may have played an important role in the antiapoptotic effect of the drug in the heart.
- Expanded the concept of cardioprotection with PDE-5 inhibitors by further showing attenuation in dilated cardiomyopathy caused by doxorubicin (DOX) or heart failure caused by permanent occlusion of coronary artery (myocardial infarction). Further showed that Viagra prevented death of heart cells, improved survival of mitochondria, preserved myofibrillar integrity, prevented heart dysfunction and EKG abnormalities that are consistent with the chronic toxicity associated with DOX.
- Elucidated the in-depth role of critical MAP kinase signaling pathway in activation of nitric oxide synthesis pathways and protein kinase G (PKG)-dependent glycogen synthase kinase -3ß inactivation in sildenafil- induced cardioprotection.
- Demonstratied that tadalafil (Cialis) causes PKG-dependent (H2S), a new gaseous molecule which plays a critical role in protection against ischemia/reperfusion injury. They are expanding the investigation to study the role of H2S in attenuation of doxorubicininduced cardiomyopathy.
- For the first time, reported the role of microRNAs (miRNAs) in cardioprotection, MicroRNAs are noncoding RNAs of 18 to 24 nucleotides that are involved in posttranscriptional regulation of protein expression. They showed that ischemic preconditioning of the heart synthesizes miRNAs that reduce injury in the heart following ischemia/reperfusion injury through upregulating cardioprotective proteins including endothelial nitric oxide synthase, heat shock protein 70 and its transcription factor HSF-1.
"Our successes and productivity are due in no small part to our talented faculty investigators, as well as the post-doctoral fellows, clinical cardiology fellows, physician scientist-track residents, and undergraduates that rotate through our lab," said Kukreja. "There are also tremendous advantages to being part of a large multidisciplinary academic medical center, where the cross-fertilization of ideas is encouraged and discoveries are translated faster into the clinical environment where patients can benefit."