Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.

The possible relationship of the atractyloside-sensitive adenine nucleotide translocase activity, oxidative phosphorylation, and the recovery of ventricular contractility following reperfusion of the ischemic isolated rat heart was studied. Five minutes of total global ischemia without reperfusion produced a significant depression in adenine nucleotide translocase in subsarcolemmal mitochondria (SLM), whereas a minimum of 10 min ischemia was required to observe a significant depression in interfibrillar mitochondria (IFM). Increasing durations of ischemia resulted in a progressively larger depression in translocase activity, with a maximum depression of approximately 75% seen in both populations following 20 min ischemia. In contrast, oxidative phosphorylation was totally unaffected in either mitochondrial population following up to 20 min of ischemia. We assessed whether translocase activity or oxidative phosphorylation were related to contractile recovery in hearts reperfused following various durations of ischemia. In SLM, translocase activity was further depressed following reperfusion compared with pre-reperfusion ischemic values, whereas with IFM only reperfusion following 5 min ischemia produced a further depression in translocase values. Oxidative phosphorylation rates of SLM and IFM were significantly depressed following reperfusion of ischemic hearts, although SLM exhibited a generally higher sensitivity in this regard. In reperfused hearts, an overall significant relationship was found between oxidative phosphorylation rate and adenine translocase activity as well as between translocase activity and post-reperfusion contractile recovery. These data show that ischemia can produce a significant depression in translocase activity in the absence of any change in oxidative phosphorylation. The results also suggest that the depression in mitochondrial ADP/ATP translocase and subsequent inhibition of oxidative phosphorylation in the reperfused heart may represent one of the important contributory mechanisms involved in cardiac failure and injury during acute ischemia and reperfusion.

transients, evoked by electrical field stimulation, were significantly prolonged in RV myocytes compared with LV myocytes, mainly because of slow decay of intracellular Ca 2ϩ concentration. The slow decay of intracellular Ca 2ϩ concentration in RV and consequent decrease in the speed of RV relaxation may promote temporal synchrony of the end of diastole in RV and LV. The preponderance of functionally silent SR Ca 2ϩ pumps in RV reflects a higher diastolic reserve required to protect and maintain RV function in the face of a sudden rise in afterload or resistance in the pulmonary circulation.calcium-adenosinetriphosphatase; phospholamban; phosphoenzyme; calcium transient; diastolic reserve THE OVERALL EFFECTIVENESS of the heart as a pump is greatly influenced by the interdependence of right ventricular (RV) and left ventricular (LV) function. LV and RV output is primarily determined by the interaction between ventricular preload, the contractile state of the myocardium, and the afterload encountered by the ventricle (16). However, the physiology and hemodynamic functions of RV in the normal state differ considerably from those of LV. For example, afterload, a major determinant of ventricular function, differs nearly sixfold between RV and LV under normal conditions (7).Cardiac adaptation to a variety of physiological stresses is inevitably linked to molecular remodeling of the sarcoplasmic reticulum (SR) Ca 2ϩ -cycling apparatus. The major Ca 2ϩ -cycling proteins in SR include the ryanodine receptor (RyR) Ca 2ϩ release channel (CRC), which is responsible for Ca 2ϩ release into cytosol on myocyte excitation to induce muscle contraction (5); sarco-(endo)plasmic Ca 2ϩ -ATPase (SERCA2a), which actively sequesters Ca 2ϩ back into SR lumen to promote muscle relaxation (18); the Ca 2ϩ -storage protein calsequestrin (27); and phospholamban (PLN), which regulates Ca 2ϩ -ATPase function (23,34,37). In its unphosphorylated state, PLN is thought to interact with Ca 2ϩ -ATPase, exerting an inhibitory effect manifested largely through a decrease in the enzyme's affinity for Ca 2ϩ ; phosphorylation of PLN by cAMP-dependent protein kinase or calmodulin (CaM) kinase is thought to disrupt this interaction, resulting in enhanced affinity of the ATPase for Ca 2ϩ and stimulation of Ca 2ϩ pump activity (23,34,37). This long-standing view has been questioned recently, and it has been reported that Ca 2ϩ , but not phosphorylation of PLN, disrupts the interaction between Ca 2ϩ -ATPase and PLN (1). Besides PLN, CaM and CaM kinase are tightly associated with cardiac SR and have been implicated in modulation of Ca 2ϩ uptake and release functions of SR through direct phosphorylation of Ca 2ϩ -ATPase (15,31,32,(43)(44)(45)(46) and RyR CRC (14,38,42).Increase in afterload of the systemic circulation is known to invoke tissue remodeling and altered Ca 2ϩ homeostasis in LV. However, the impact of physiological load of RV on SR function, to our knowledge, has not been studied. As a first step in exploring the mechanisms of RV adaptation to stress...

The aim of this study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the host myocardium on bone marrow mesenchymal stromal cells (MSC) migration to the ischemic myocardium and whether stromal cell-derived factor-1a (SDF-1a) contributes to eNOSmediated MSC migration. MSCs and coronary microvascular endothelial cells were isolated from adult wild-type (WT) mouse bone marrow and hearts, respectively. Cultured neonatal cardiomyocytes from WT, eNOS 2/2 , and eNOS overexpressing transgenic (Tg) mice were subjected to anoxia and reoxygenation (A/R), and the conditioned medium was used as a chemoattractant for in vitro transendothelial migration assay. MSC migration was decreased in the presence of conditioned medium derived from eNOS 2/2 cardiomyocytes but increased in the presence of eNOS-Tg conditioned medium. SDF-1a expression was decreased in eNOS 2/2 but increased in eNOS-Tg cardiomyocytes following A/R and in the myocardium following ischemia/reperfusion (I/R). SDF-1a expression was cGMP-dependent as inhibition of soluble guanylyl cyclase decreased SDF-1a expression in WT cardiomyocytes. MSCs expressed very low levels of eNOS proteins compared with the adult myocardium. To examine MSC migration in vivo, MSCs derived from mice expressing enhanced green fluorescence protein (EGFP 1 ) were intravenously administered to WT mice subjected to myocardial I/R. EGFP 1 cells in the ischemic region were decreased in eNOS 2/2 but increased in eNOS-Tg compared with WT hearts. MSC treatment improved cardiac function following I/R in WT but not in eNOS 2/2 mice. In conclusion, eNOS in the host myocardium promotes MSC migration to the ischemic myocardium and improves cardiac function through cGMP-dependent increases in SDF-1a expression. STEM CELLS 2009;27:961-970 Disclosure of potential conflicts of interest is found at the end of this article.

Anesthetic concentrations of propofol maintain the capacity of brain cells to extrude protons during oxidative stress. However, if intracellular acidification occurs nonetheless, then propofol's protection of glutamate clearance mechanisms from oxidative damage becomes attenuated, and extracellular glutamate concentration may increase to neurotoxic levels.