Diabetes has emerged as a major threat to worldwide health. The increasing incidence of diabetes in young individuals is particularly worrisome given that the disease is likely to evolve over a period of years. In 1972, the existence of a diabetic cardiomyopathy was proposed based on the experience with four adult diabetic patients who suffered from congestive heart failure in the absence of discernible coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism. The exact mechanisms underlying the disease are unknown; however, an important component of the pathological alterations observed in these hearts includes the accumulation of extracellular matrix (ECM) proteins, in particular collagens. The excess deposition of ECM in the heart mirrors what occurs in other organs such as the kidney and peritoneum of diabetics. Mechanisms responsible for these alterations may include the excess production, reduced degradation, and/or chemical modification of ECM proteins. These effects may be the result of direct or indirect actions of high glucose concentrations. This article reviews our state of knowledge on the effects that diabetes-like conditions exert on the cells responsible for ECM production as well as relevant experimental and clinical data.

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.

To determine the relation between local myofiber anatomy and local deformation in the wall of the left ventricle, both three-dimensional transmural deformation and myofiber orientation were examined in the anterior free wall of seven canine left ventricles. Deformation was measured by imaging columns of implanted radiopaque markers with high-speed, biplane cineradiography (16 mm, 120 frames/sec). Hearts were fixed at end diastole and sectioned parallel to the local epicardial tangent plane to determine the transmural distribution of fiber directions at the site of strain measurement. The principal direction of deformation associated with the greatest shortening was compared with the local fiber direction in the outer (21 ± 8 % of the wall thickness from the epicardium) and inner (65 ±9%) halves of the wall. Although the fiber direction varied substantially with depth from the epicardium, the principal direction did not. In the outer half of the wall, fiber direction averaged-8 ± 24°, while the principal direction averaged-33 ±24° from circumferential (counterclockwise angles are positive). In the inner half, fiber direction averaged 69 ±10°, while the principal direction averaged-22 ±21°. Therefore, while fiber and principal directions were not substantially different hi the outer half, the greatest shortening occurred orthogonally to the fiber direction hi the inner half. Normal and shear strains measured in a cardiac coordinate system (circumferential, longitudinal, and radial coordinates) were rotated (transformed) to "fiber" coordinates hi both halves of the wall. In the outer half, normal strains observed in the fiber (-0.09 ±0.04) and cross-fiber (-0. 0 4 ±0.04) directions were not significantly different (paired t test, p<0.05). In the inner half, more than twice as much strain occurred in the cross-fiber (-0.17 ± 0.03) than in the fiber direction (-0.06 ± 0.06). Moreover, the only shear strain that remained substantial after transformation was transverse shear in the plane of the fiber and radial coordinates. These results suggest that both reorientation and cross-sectional shape changes of myofibers or the interstitium may contribute to the large wall thickenings observed during contraction, particularly in the inner hah* of the ventricular wall. (Circulation Research 1988;63:550-562) T he way in which myofibers lying at different depths in the heart wall and having different orientations interact during contraction is not known. It is well known, however, that there is an extensive collagenous network surrounding the myocyte and collagen struts between myocytes. 12 Moreover, the direction of the myofibers, which varies continuously with depth spanning more than 100° across the anterior free wall of the canine left ventricle, 34 is neither altered by large changes in ventricular mass or shape 3 nor affected greatly by

Non-technical summary During exercise, skeletal muscle performance depends in great part on the use of aerobic metabolism to supply the energetic demand of contractions. Endurance training increases the muscle aerobic capacity, which is not only associated with enhanced exercise performance, but also with a decreased risk of cardiovascular and metabolic diseases. Recently, it has been shown that regular use of small doses of dark chocolate may result in similar health benefits to exercise training. We show here that mice fed for 15 days with (-)-epicatechin (present in dark chocolate) had improved exercise performance accompanied by: (1) an increased number of capillaries in the hindlimb muscle; and (2) an increased amount of muscle mitochondria as well as signalling for mitochondrial biogenesis. These results suggest that (-)-epicatechin increases the capacity for muscle aerobic metabolism, thereby delaying the onset of fatigue. These findings may have potential application for clinical populations experiencing muscle fatigue. AbstractThe flavanol (-)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (-)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water-exercise (W-Ex), (3) (-)-epicatechin ((-)-Epi), and (4) (-)-epicatechin-exercise ((-)-Epi-Ex). Animals received 1 mg kg −1 of (-)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (∼50%) and enhanced in situ muscle fatigue resistance (∼30%) were observed with (-)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (-)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (-)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (-)-epicatechin alone. These findings indicate that (-)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (-)-epicatechin and its potential clinical application as an exercise mimetic.

Background. Cardiac hypertrophy results in an increased deposition of the extracellular matrix (ECM) proteins fibronectin and collagen. Recent evidence indicates that angiotensin II (Ang II) might have an important role in the development of myocardial fibrosis accompanying cardiac hypertrophy. We sought to determine whether fibroblasts of cardiac origin (isolated from neonatal and adult animals) express

Cardiac hypertrophy induced by pressure overload is accompanied by increases in the deposition of extracellular matrix (ECM) proteins. We wanted to determine in this study whether changes in mRNA coding for transforming growth factor (TGF)-beta 1, TGF-beta 3, and the ECM proteins, fibronectin and collagen, occur during the early phases of cardiac hypertrophy. Steady-state mRNA levels were determined in sham-operated and thoracic-banded hypertrophied rat myocardium from 6 h to 30 days after surgery. TGF-beta 1 mRNA increased significantly (1.7-fold vs. control) 12 h after aortic banding, decreasing to control levels by 14 days. No significant changes were observed for TGF-beta 3 message. Fibronectin mRNA levels increased twofold at day 1 and peaked to approximately threefold at day 3. Type I and III collagen mRNA expression was similar to control levels at day 1 but increased significantly 3 days after banding. Cardiac hypertrophy also resulted in an induction of mRNA for an embryonic isoform of fibronectin (EIIIA+) that is generated through alternative splicing of the gene. These findings indicate that, with myocardial hypertrophy, mRNAs for fibronectin are increased as early as 1 day after banding, which may allow for an initial increase in the production of fibronectin followed by the deposition of collagen. These increased mRNA levels for the ECM proteins are preceded by marked increases in TGF-beta 1 mRNAs.

Abstract-Recent reports indicate that (Ϫ)-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 (Ϫ)-epicatechin activates eNOS remains unclear. In this study, we proposed to identify the intracellular pathways involved in (Ϫ)-epicatechin-induced effects on eNOS, using human coronary artery endothelial cells in culture. Key Words: flavonoids Ⅲ ischemia Ⅲ polyphenols Ⅲ endothelial cells Ⅲ endothelial nitric oxide synthase C ardiovascular diseases (CVD) are is a leading cause of morbidity and mortality, affecting Western industrialized countries as well as developing countries. 1,2 CVD imposes major direct and indirect costs on health care systems, ranging from hospitalizations, drugs, and rehabilitation services to losses of productivity due to premature mortality and short-and long-term disability. 1 The incidence of CVD continues to increase; thus, it is important to identify potential therapeutic agents to prevent and treat CVD.CVD is importantly linked to endothelial cell dysfunction. Endothelial cell dysfunction is associated with conditions, such as obesity, smoking, diabetes, and hormonal changes. The vascular endothelium mediates many important physiological functions, such as responses to shear stress, angiogenesis, vascular remodeling, inflammation, and coagulation. It also participates in metabolic and synthetic processes. 3 A key modulator of endothelial cell activity is nitric oxide (NO), which under physiological conditions is mainly produced by the endothelial nitric oxide synthase (eNOS) isoform. NO regulates vascular tone, proliferation of vascular smooth muscle cells, and hemostasis, among other important functions. Disruptions in the physiological production of NO triggers endothelial cell dysfunction, resulting in an increased susceptibility to CVD. 4 Therefore, strategies aimed at "physiologically" increasing NO bioavailability are promising for the prevention and therapy of CVD.The induction of NO synthesis by flavonoid-containing compounds has received widespread attention, as their effects appear to positively impact CVD. Epidemiological studies indicate that the regular dietary intake of plant-derived foods and beverages high in flavonoids is inversely associated with the incidence of CVD. 5 Although these compounds are pleiotropic in nature, many of their effects may be explained by improving endothelial function. The regular consumption of cacao products high in flavonoid content has also been demonstrated to provide beneficial cardiovascular effects. 5 Natural cacao products are rich in monomeric and polymeric forms of the flavonoids (Ϫ)-epicatechin (EPI) and catechin (60/40 ratio) and can contain up to 10% flavonoids by weight. 6 The consumption of cacao products can ameliorate

The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In an effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were evaluated using an isolated perfused rat heart system. Hearts were subjected to ischemia reperfusion injury, and recovery of contractile function was examined. In this model, only one of the two MMPi showed significant and sustained heart recovery, demonstrating that the choice of ZBG can have a significant effect in a relevant pathophysiological endpoint.