UC San Diego

The tetracycline class of antibiotics, which include the members doxycycline (DOX) and minocycline (MIN), have additional biological effects independent of their antimicrobial actions, of which inhibition of matrix metalloproteinases (MMPs) is the best characterized. Tetracyclines are also capable of scavenging reactive oxygen species (ROS) and inhibiting apoptosis and likely possess other undescribed important biological properties. These non-antimicrobial actions of the tetracyclines promote cell survival in several models of neuronal cell injury. These biochemical processes targeted by the tetracyclines are also important in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury and adverse ventricular remodeling following myocardial infarction (MI). Therefore, I hypothesized that tetracyclines would elicit cytoprotective and anti-remodeling effects following myocardial ischemic injury. The work described here explores the capacity of DOX and MIN to improve myocardial survival, structure, and function following injury and examines their underlying mechanisms. First, it was shown that DOX inhibited adverse remodeling post-MI by inhibiting MMP activation. Second, DOX reduced infarct size following I/R injury in vivo by a mechanism independent of MMP inhibition. Using myocyte cell cultures it was found that DOX improved myocyte survival by inhibiting plasmin-mediated proteolysis of beta-1D- integrin, thereby preserving myocyte-matrix interactions. Third, MIN, but not DOX, reduced infarct size in isolated, perfused rat hearts subjected to I/R, potentially due to its ability to inhibit opening of mitochondrial permeability transition pore. Fourth, MIN attenuated myocardial stunning and improved coronary artery flow in isolated, perfused rat hearts independent of MMP inhibition. MIN treatment was associated with increased peroxynitrite generation, suggesting that MIN promoted the formation of peroxynitrite-derived nitric oxide donor compounds capable of promoting vasodilation. Taken together, these studies demonstrate that DOX and MIN target different biochemical processes involved in the pathogenesis of myocardial I/R injury and remodeling. The lipophilic nature of MIN allows it to have greater impact on intracellular processes, such as inhibiting MPTP opening and increasing peroxynitrite generation. The less lipophilic nature of DOX confines its actions to the extracellular environment, with plasmin and MMP inhibition among its major effects