Abstract

Cardiac injury, pore-forming toxins, calcium influx

Cardiac muscles and conduction system are very sensitive to interruption of plasma membrane integrity due to uncontrollable ion diffusion. There are many types of toxins that could bind to cell membrane and form pores to allow ion diffusion cross the membrane. However, the effects and underlying mechanisms of those pore-forming toxins on cardiac functions have not been systemically investigated.

In this work, we investigated the effects of extracellular histones (endogenous) and pneumolysin (exogenous) on cardiomyocytes and underlying molecular mechanisms using cultured cardiomyocytes and mouse models. We found that both toxins could bind to cardiomyocyte membrane and caused large inward currents which altered membrane potentials. This led arrhythmia of cultured cardiomyocytes and mice infused with isolated toxins. In addition, circulating troponins, a marker of cardiac injury, were significantly elevated and the contractile performance of cardiomyocytes was also reduced.

Further investigation, we found that the uncontrollable calcium influx mainly increased diastolic intracellular calcium concentration and resulted in calcium transient reduction. However, the calcium-dependent protein kinase C, particularly PKC±, was significantly activated by calcium influx. Consequently, the phosphorylation of Troponin I was enhanced, which is known to correlate to contractile reduction. In addition, the phosphorylation levels of P38 and JNK kinases, and endoplasmic reticulum (ER) stress levels were also increased. Those changes may contribute to the suppression of cardiomyocyte contractility too.

In conclusion, the endogenous pore-forming toxins, such as circulating histones released after extensive tissue injury, and exogenous pore-forming toxins released during bacterial infection, may play important roles in the development of cardiac complications in many types of critical illnesses. In certain scenario, such as sepsis, both endogenous and exogenous toxins may synergistically harm the heart and cause severe complications to lead to early death of patients. Therefore more intensive investigation should be carried out to clarify their effects in patients as well as their molecular mechanisms in order to develop effective tools to diagnose, prevent and treat those cardiac complications induced by pore-forming toxins.