Zhang et al. Journal of Translational Medicine

Diabetes is associated with numerous “secondary complications” including premature heart disease, renal failure, critical limb ischemia (an advanced form of peripheral artery disease) and diabetic retinopathy. One of the common features of these secondary complications is that they are all associated with low levels of circulating endothelial progenitor cells. We have previously discussed the interaction between inflammation and low levels of circulating endothelial progenitor cells http://www.translational-medicine.com/content/7/1/106. It appears that the uncontrolled sugar levels in the blood cause generation of modified proteins, which initiate low level, chronic inflammation. One of the major mechanisms by which sugar- modified proteins induce inflammation is by stimulating a molecular signaling protein called Toll like receptor (TLR)-4. Generally TLR-4 is used by the body to sense “danger”, that is, to sense pathogens, tissue injury, or various factors that may negatively affect the well-being of the host.

In a collaborative study between Stem Cell Institute Panama, Medistem, and the University of Western Ontario, Canada, it was observed that TLR-4 is associated with induction of heart cell (cardiomyocyte) death in diabetic animals. The scientists demonstrated that suppressing the gene encoding for TLR-4 resulted in prevention of heart disease. The results were published in the article Zhang et al. Prevention of hyperglycemia-induced myocardial apoptosis by gene silencing of Toll-like receptor-4. J Transl Med. 2010 Dec 15;8(1):133. TLR-4 is known to recognize bacterial endotoxin, fragments of degraded extracellular matrix, as well as the stress protein HMBG-1.

In the current experiment, mice were made diabetic by administration of the islet-specific toxin streptozotocin. Diabetic mice were treated with double stranded RNA specific to the gene encoding TLR4. It is known that when cells are treated with double stranded RNA, the gene that is similar to the double strand is silenced. This process is called “RNA interference”.

Seven days after mice became diabetic, as evidenced by hyperglycemia, the level of TLR4 gene in myocardial tissue was significantly elevated. This suggested that not only does hyperglycemia activate TLR4, which was previously known, but that expression of this pro-inflammatory marker actually is increased. Indeed it may be possible that triggers of TLR4 actually act in an autocrine manner in order to increase cell sensitivity

In order to determine whether TLR4 was associated with the cause of cardiomyocyte death, animals were administered the double stranded RNA in order to suppress levels of TLR4. When this was performed the level of cardiomyocyte death was markedly reduced. This is an important finding since usually scientists think of TLR4 as a molecule that activates inflammation through stimulation of the immune

The authors conclude by stating that new evidence is presented suggesting that TLR4 plays a critical role in cardiac apoptosis. This is the first demonstration of the prevention of cardiac apoptosis in diabetic mice through silencing of the TLR4 gene.

The research finding that TLR4 is implicated in death of cardiac cells means that agents that suppress it, such as double stranded RNA, may be useful for incorporation into stem cells in order to make the cardiac cells that are derived from the stem cells resistant to death induced by conditions of stress such as hyperglycemia.