Synergistic effect of inhibitors of MMPs and ROS-dependent modifications of contractile proteins on protection hearts subjected to oxidative stress.

Cardiac ischemia, followed by reperfusion, often results in the development of cardiac contractile dysfunction that limits the recovery prognosis of patients. The current goal of pharmacological therapy in the course of ischemic heart disease is to improve the oxygen supply/demand ratio for the heart. Cardiac contractile proteins such as myosin light chain 1 and 2 (MLC1 and MLC2) and troponin I, play a significant role in the regulation of force development. It has been shown that MLC1 can be nitrated, S-nitrosylated, as well as phosphorylated. These posttranslational modifications (PTMs) of MLC1 are associated with an increase in the affinity for the proteolytic enzyme matrix metalloproteinase-2 (MMP-2) resulting in an increased degradation of MLC1 that corresponds with the development of cardiac contractile dysfunction. The degree of MLC1 degradation is associated with the degree of mechanical dysfunction in the ischemic heart. Pharmacological regulation of the PTM status of cardiac contractile proteins can be achieved by inhibition of phosphorylation, nitration, or S-nitrosylation. Most pharmacological approaches for protecting the heart against ischemia/reperfusion (I/R) injury are based on the use of a single drug at full protective dose, targeting only a single molecular mechanism involved in the development of contractile dysfunction. As such, this approach often creates side effects associated with interruption of normal physiological processes. It is hypothesized that simultaneous pharmacological reduction of reactive oxygen species (ROS)-dependent PTMs of contractile proteins such as nitration/nitrosylation and/or phosphorylation, together with the pharmacological inhibition of the activity of MMPs, will protect the heart from I/R injury through synergistic or additive drug effects while also enabling lower doses to reduce interruption of normal physiological processes and limit side effects.