Transplantation of adult stem cells into the heart after a heart attack has shown remarkable promise as a treatment for heart patients. The implanted stem cells improve heart function, reinforce heart structure, improve blood circulation in the heart, and reduce the size of the heart scar. Such treatments. however, are hampered by the lack of persistence of implanted stem cells. Only a vast minority of the implanted stem cells survive in the inhospitable environment of the infarcted heart, and the massive cell die-off limits the efficacy of stem cell transplants in the heart.
Fortunately, there are ways to allay this problem. Genetically engineering stem cells to express proteins known to enhance cell survival is one way to ensure that implanted cells survive when implanted. However, getting FDA approval for a clinical trial with genetically-engineered cells will prove to be immensely difficult. A more promising approach is to pretreat the cells with various growth factors, growth conditions or drugs to precondition them to survive in the heart. To that end, scientists at the Davis Heart and Lung Research Institute at Ohio State University have used a commonly prescribed heart drug called “carvedilol” to enhance the survive of bone marrow mesenchymal stem cells in the heart.
Faternat Hassan and his colleagues in the laboratory of Mahmood Khan treated mesenchytmal stem cells (MSCs) from rats with carvedilol and a related drug called “atenolol.” These drugs are members of a drug category called “beta-blockers.”
Beta-blockers are given to lower blood pressure, or to protect the heart after a heart attack from undergoing further deterioration. They bind to the receptors for epinephrine and norepinephrine and block them, which slows the heart down and reduces blood pressure. After a heart attack, however, Beth Haebecker at Oregon Health and Science University has shown that the sympathetic nerves to the heart make very large amounts pf norepinephrine and this is responsible for the remodeling and eventual deterioration of the heart. Beta-blockers can prevent this norepinephrine-based deterioration of the heart.
Over ten years ago, Yue et al. (1992) and Feuerstein (1998) showed that carvedilol has the ability to quench the deleterious effects of damaging molecules. Therefore, carvedilol might protect stem cells from dying in the heart after transplantation.
To begin, Khan’s group cultured MSCs with carvedilol and atenolol for one hour and then subjected the cells to chemical stress by treating them with hydrogen peroxide. The carvedilol-treated cells survived the hydrogen peroxide treatment much better than either the atenolol-treated MSCs or the negative controls that were not pretreated with anything.
For their next experiment, they divided into five groups of six animals each. The first group was operated on but were not give heart attacks. The second group was given heart attacks and no further treatments. The third group was given carvedilol (5 mg/kg body weight) after the heart attack. The fourth group, was MSC treatments, and the fifth group received MSC transplantations plus carvedilol at the previously mentioned dosages. The results showed that the MSC + carvedilol group fared substantially better than all the rest (except for the sham operated group). The heart structure and heart physiology were far superior in the MSC + carvedilol group.
Finally, Khan’ group made a remarkable discovery. Carvedilol prevented the heart from undergoing extensive cell death and decreased the formation of scar tissue. When combined with MSCs, carvedilol’s effect on cell death was amplified. Further investigation demonstrated that carvedilol prevented activation of a protein called “caspase-3.”
Caspases are proteins that degrade other proteins, but they are activated when the cell is damaged beyond all reasonable expectations of repair and the only fitting response for the cell is to die. This process of programmed cell death is called “apoptosis.” The induction of apoptosis is, as you might guess, very tightly controlled, and one of the main regulators of the initiation of apoptosis are the caspases. Caspases exist as inactive enzymes in the cell, but they are activated if the cells is exposed to drugs,conditions, or chemicals that induce cell death. There are three caspases that activate the rest of them and they are caspase 3, 8, & 9, and of these, caspases 3 and 9 are the most important.
Carvedilol treatment caused a significant down-regulation of caspase-3 in heart muscle cells after a heart attack. Furthermore, it prevented the expression of caspase-3 in implanted MSCs, thus increasing MSC survival. Additionally, genes that are known to improve cell survival were also activated in heart muscle cells after carvedilol and MSC treatment.
Thus carvedilol did double duty. It helped the ailing heart, but it also helped the heart help itself by preventing the untimely death of transplanted MSCs. This allowed the MSCs to work their healing processes for a much longer time. The final result was that the carvedilol + MSC-implanted rats showed hearts that were in much better shape than the those in the other groups with the exception of the sham-operated group.
This also suggests that carvedilol should be used with transplanted MSCs in the next clinical trial that utilizes transplanted MSCs.