Journal of Cardiothoracic-Renal Research最新文献

Background

Heart failure is approaching epidemic proportions. However, DNA damage in the failing myocardium is not directly addressed yet. 8-Oxo-7,8-dihydrodeoxyguanine (8-oxoG) is a stable marker of DNA damage. The human Mut-Y homologue (hMYH) is a DNA mismatching repair enzyme promoting DNA reconstruction. The current study was designed to investigate whether DNA damage and repair as reflected in the levels of 8-oxoG and hMYH play an important role in the failing myocardium.

Methods

Donor and failing human myocardium were obtained from hearts of patients undergoing cardiac transplantation. DNA damage was determined by the presence of 8-oxoG. The protein level, activity, and expression of hMYH were determined by Western blot, the DNA gel-retardation binding assay and immunohistochemical staining (IHCS). The levels of apoptosis and apoptosis-related genes such as p53, p21-WAF, and caspase-3 were determined by TUNEL assay and IHCS.

Results

The levels of 8-oxoG indicating DNA damage significantly increased in the myocardium of failing hearts compared with donor subjects. On the other hand, the protein level and activity of the DNA repair enzyme, hMYH, was significantly decreased in CHF patients compared to donor subjects. Furthermore, apoptosis and apoptosis-related genes such as p53, p21-WAF, and caspase-3 were markedly increased in CHF myocardium.

Conclusion

Ongoing DNA damage is insufficiently repaired in the myocardium of failing hearts. This appears to be a major pathway responsible for myocardial failure in humans.

Diabetic cardiomyopathy is a major threat to increased morbidity and mortality in population with diabetes. A number of hypotheses have been postulated for the pathogenesis of diabetic cardiomyopathy including defective polyol pathway, reduced energy production due to decrease in mitochondrial respiration and pyruvate dehydrogenase activity, accumulation of advanced glycation end-product (AGE) and free radical species, activation of protein kinase C (PKC) as well as enhanced hexosamine flux. These culprit machineries may result in impaired intracellular Ca²⁺ handling in cardiomyocytes due to compromised contractile and intracellular Ca²⁺ regulatory proteins such as myosin, titin, sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA), phospholamban and Na⁺–Ca²⁺ exchanger. Nevertheless, neither precise pathogenesis of the disease nor effective therapeutic remedy is available for diabetic cardiomyopathy. In this issue of JCRR, Ding et al. demonstrated an established role of endothelin-1 (ET-1) in diabetes-induced cardiomyocyte dysfunction using treatment of dual ET_A/ET_B receptor antagonist bosentan. Their results have conclusively consolidated the logic of ET-1 and its membrane receptors as a novel pathophysiological cue for the development of diabetic cardiomyopathy.

Cardiac stem cell therapy is emerging as a potential novel treatment for patients with heart disease. Experimental studies and clinical trials have shown that stem cell transplantation can achieve certain degrees of success in enhancing myocardial perfusion, repair or regeneration, leading to improvement of cardiac function. Different types of stem cells including those from embryonic and adult tissues have been tested, and each stem cell type has advantages and disadvantages. The stem cell type(s) most suitable for cardiac cell therapy is hard to define, but such cells are usually characterized by their high potential for survival, growth, and differentiation as well as integration into the host tissue. Selection of proper delivery methods according to lesion size and location is also a critical factor for the success of stem cell therapy. Preliminary data from experimental stem cell research and clinical trials for cardiac stem cell therapy are controversial, yet encouraging.