Chapters authored
Evidence for the Role of Cell Reprogramming in Naturally Occurring Cardiac Repair
Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. If untreated, increased pulmonary vascular resistance kills patients within several years due to right heart failure. Even with the currently available therapies, survival durations remain short. By the time patients are diagnosed with this disease, the damage to the right ventricle (RV) has already developed. Therefore, agents that repair the damaged RV have therapeutic potential. We previously reported that cardiac fibrosis that occurs in the RV of adult Sprague–Dawley rats with PAH could naturally be reversed. We herein investigated the mechanism of this remarkable cardiac repair process. Counting of cardiomyocytes showed that the elimination of cardiac fibrosis is associated with the increased RV myocyte number, suggesting that new cardiomyocytes were generated. Immunohistochemistry showed the expression of α-smooth muscle actin and Sox-2 in RV myocytes of rats with PAH. Transmission electron microscopy detected the structure that resembles maturing cardiomyocytes in both the RV of PAH rats and cultured cardiomyocytes derived from induced pluripotent stem cells. We propose that the damaged RV in PAH can be repaired by activating the cell reprogramming mechanism that converts resident cardiac fibroblasts into induced cardiomyocytes.
Part of the book: Muscle Cell and Tissue
Strategies to Treat Pulmonary Hypertension Using Programmed Cell Death-Inducing Anti-Cancer Drugs without Damaging the Heart
Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. By the time patients are diagnosed with PAH, thickening of pulmonary arterial (PA) walls and the narrowing of vascular lumen have already developed due to the abnormal growth of pulmonary vascular cells, contributing to the elevated pulmonary vascular resistance and the right ventricle (RV) damage. Therefore, agents that eliminate excess pulmonary vascular wall cells have therapeutic potential, and the apoptosis-based therapy using anti-cancer drugs may be promising for the treatment of PAH. However, cell death agents could also exert adverse effects including cardiotoxicity, complicating the development of such therapies for PAH patients who already have the damaged heart. We tested the concept that programmed cell death-inducing anti-cancer drugs may reduce the PA wall thickening using rat models of PAH. We found that: (i) The treatment of PAH animals with anthracycline-, proteasome inhibitor- or Bcl-2 inhibitor-classes of anti-cancer drugs after the pulmonary vascular remodeling had already developed resulted in the reversal of PA wall thickening and opened up the lumen; (ii) These effects were accompanied by the apoptosis of PA wall cells in PAH rats, but not in normal healthy rats, suggesting the anti-cancer drugs selectively kill remodeled vascular cells; (iii) The RV affected by PAH was not further damaged by anthracyclines or proteasome inhibitors; (iv) While the left ventricle (LV) was damaged by these drugs, we identified cardioprotective agents that protect the heart against drug-induced cell death without affecting the efficacy to reverse the PA remodeling; and (v) docetaxel, not only reversed pulmonary vascular remodeling without exerting RV or LV toxicity, but also repaired the RV damage caused by PAH. Thus, the inclusion of programmed cell death-inducing anti-cancer drugs should be considered for treating PAH patients.
Part of the book: Muscle Cell and Tissue