There must be something unique about a class of drugs (discovered and developed in the mid-1940s) where there are more than 130 ongoing clinical trials currently listed. Tetracyclines were developed as a result of the screening of soil samples for antibiotic organisms. The first of these compounds chlortetracycline was introduced in 1948. Soon after their development tetracyclines were found to be highly effective against various pathogens including rickettsiae, Gram-positive, and Gram-negative bacteria, thus, becoming a class of broad-spectrum antibiotics. The mechanism of action of tetracyclines is thought to be related to the inhibition of protein synthesis by binding to the 30S bacterial ribosome. Tetracyclines are also an effective anti-malarial drug. Over time, many other “protective” actions have been described for tetracyclines. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Its mechanism of action appears to relate to specific effects exerted on apoptosis signaling pathways. Another tetracycline, doxycycline is known to exert antiprotease activities. Doxycycline can inhibit matrix metalloproteinases, which contribute to tissue destruction activities in diseases such as gingivitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as oxygen radical scavengers and anti-inflammatory agents. This increasing volume of published work and ongoing clinical trials supports the notion that a more systematic examination of their possible therapeutic uses is warranted. This review provides a summary of tetracycline's multiple mechanisms of action and while using the effects on the heart as an example, this review also notes their potential to benefit patients suffering from various pathologies such as cancer, Rosacea, and Parkinson's disease.

Recent reports indicate that (−)-epicatechin can exert cardioprotective actions, which may involve endothelial nitric oxide synthase (eNOS)-mediated nitric oxide production in endothelial cells. However, the mechanism by which (−)-epicatechin activates eNOS remains unclear. In this study, we proposed to identify the intracellular pathways involved in (−)-epicatechin-induced effects on eNOS, using human coronary artery endothelial cells in culture. Treatment of cells with (−)-epicatechin led to time- and dose-dependent effects that peaked at 10 minutes at 1 μmol/L. (−)-Epicatechin treatment activates eNOS via serine 633 and serine 1177 phosphorylation and threonine 495 dephosphorylation. Using specific inhibitors, we have established the participation of the phosphatidylinositol 3-kinase pathway in eNOS activation. (−)-Epicatechin induces eNOS uncoupling from caveolin-1 and its association with calmodulin-1, suggesting the involvement of intracellular calcium. These results allowed us to propose that (−)-epicatechin effects may be dependent on actions exerted at the cell membrane level. To test this hypothesis, cells were treated with the phospholipase C inhibitor U73122, which blocked (−)-epicatechin-induced eNOS activation. We also demonstrated inositol phosphate accumulation in (−)-epicatechin-treated cells. The inhibitory effects of the preincubation of cells with the calmodulin-dependent kinase II (CaMKII) inhibitor KN-93 indicate that (−)-epicatechin-induced eNOS activation is at least partially mediated via the Ca ²⁺ /CaMKII pathway. The (−)-epicatechin stereoisomer catechin was only partially able to stimulate nitric oxide production in cells. Together, these results strongly suggest the presence of a cell surface acceptor-effector for the cacao flavanol (−)-epicatechin, which may mediate its cardiovascular effects.

Background— Myocardial infarction (MI) is associated with early metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation. We hypothesized that preserving the original ECM of the infarcted left ventricle (LV) by use of early short-term doxycycline (DOX) treatment preserves cardiac structure and function. Methods and Results— LV morphometry and function were measured in 3 groups of rats (sham, MI, and MI+DOX). DOX (30 mg/kg per day) was given orally 48 hours before and 48 hours after MI. Rats were examined at 2 and 4 weeks after MI. By 4 weeks, DOX significantly decreased ( P <0.05 versus MI) the heart weight to body weight ratio, myocyte cross-sectional area, and internal LV diameter, whereas it preserved anterior wall thickness within the infarct. Collagen/muscle area fraction did not change in the region of the infarct/scar. Parallel left shifts (versus MI) were observed in pressure-volume relationships of DOX MI rats at all pressures. DOX treatment also shifted passive epicardial strains within the scar area toward normal values. No differences were observed in LV end-diastolic or peak systolic pressures, peak positive or negative LV dP/dt, or isovolumic relaxation rates. Assessment of LV global MMP and MMP-2/9 activities 1 hour after MI using fluorescent probes yielded significant differences with DOX. Conclusions— Brief, early MMP inhibition after MI yields preservation of LV structure and global as well as scar area passive function, supporting the concept that preserving the original ECM early after coronary occlusion lessens ventricular remodeling.

(‐)‐Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi‐rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi‐rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi‐rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi‐rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. Clin Trans Sci 2012; Volume 5: 43–47