Efficiency of PARP Inhibitors in Cardiovascular Diseases
Cardiovascular diseases such as myocardial ischemia, circulatory shock, atherosclerosis and various types of heart failure result in the formation of components such as reactive oxygen and nitrogen in the myocardial cells. These components initiate a series of bio-chemical reactions that finally results in the necrosis of the cells, an undesired effect. Studies have shown that PARP inhibitors play role in regulating the bio-chemical reactions taking place after a cardiovascular disease. This article presents an overview of the biochemistry of the cardiovascular diseases and how Poly adenosine phosphate ribose polymerase (PARP) inhibitors regulates those reactions and finally prevents necrosis of the myocardial cells.
The Biochemistry of cardiovascular diseases
As mentioned reactive species such as nitrogen and reactive oxygen are formed during cardiovascular diseases. These reactive components cause DNA damage and subsequent activation of PARP family of enzymes that play role in repair of the damaged DNA. However, over activation of the PARP enzymes results in depletion of its substrate NAD+ and ultimately the respiratory processes glycolysis and electron transport chain. As a result the formation of ATP gets impaired and finally results in the death of endothelial cells of the heart tissue. Now, let us see what scientists are trying to prevent the necrosis of the cardiomyocytes.
Use of PARP inhibitors in cardiovascular diseases
Exposure of the cell to agents causing DNA damage results forces the cell to enter any one of the following three pathways.
- Moderate DNA damaging agents result in activation of PARP-1 which assists in DNA repair by interacting with the enzymes XRCC1 and DNA-PK. PARP (Poly adenosine phosphate ribose polymerase) is a protein with three domains namely the DNA binding domain, catalytic domain and the auto modification domain. PARP recognizes the damaged DNA and can bind to both single stranded and double stranded DNA breaks. After binding to the breaks, it initiates the cleavage of NAD+ and imparts negative charge to the histones. These two actions aid in DNA repair and regulation of transcription process. After the DNA repair the cell continues its normal functioning without passing on the mutated genes.
- Exposure of the cellular DNA to strong DNA damaging agents induces the apoptotic cellular lysis. In this pathway, cleavage of PARP in to separate domains prevents its ability to repair DNA. As a result the cellular energy is conserved this in turn is utilized for apoptotic cell death.
- Increased DNA damage triggered by reactive agents such as nitrogen components and reactive oxygen as in case of cardiovascular diseases triggers the necrotic cell death due to over activation of PARP. As a result of over activation, the cellular energy is totally consumed and even the glycolysis and electron transport chain that generate the cellular energy also remain inhibited forcing the cell to necrosis.
So, for normal cellular functioning of cardiac cells it is essential to prevent the cells from entering the third pathway after a severe cardiac shock. This can be done by inhibiting the functioning of PARP to save the cellular energy and encourage the cell to either function normally or undergo apoptosis.
Studies have shown that genetic deletion of PARP-1 or inhibition of PARP through drugs elevates hypertrophy response, cardiovascular dysfunction and heart failure. Many of the PARP inhibitors such as INO-1001 are under clinical trials. They are being studied to use efficiently in treating cardiovascular diseases and cancer.