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1.
Am J Physiol Heart Circ Physiol ; 308(6): H651-63, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25599572

ABSTRACT

Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and ß2-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.


Subject(s)
Cytoskeleton/metabolism , Heart Failure/metabolism , Mitochondria, Heart/metabolism , Myocytes, Cardiac/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , Ventricular Dysfunction, Left/metabolism , Animals , Antioxidants/pharmacology , Cytoskeleton/drug effects , Cytoskeleton/pathology , Desmin/metabolism , Disease Models, Animal , Heart Failure/drug therapy , Heart Failure/pathology , Heart Failure/physiopathology , Male , Membrane Potential, Mitochondrial , Mitochondria, Heart/drug effects , Mitochondria, Heart/ultrastructure , Myocardial Contraction , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/ultrastructure , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Time Factors , Tubulin/metabolism , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacology , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathology , Ventricular Function, Left
2.
Circ Heart Fail ; 7(1): 194-202, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24297688

ABSTRACT

BACKGROUND: There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into ingenuity pathway analysis in patients with isolated MR. METHODS AND RESULTS: Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared with 13 normal controls. Cine-MRI was performed in 31 patients before surgery to measure LV function and volume from serial short-axis summation. LV end-diastolic volume was 2-fold (P=0.005) higher in MR patients than in normal controls, and LV ejection fraction was 64±7% (50%-79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in ß-adrenergic, cAMP, and G-protein-coupled signaling, whereas there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR versus control left ventricles. However, mRNA and protein levels of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold, respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal left ventricles and its marked upregulation in MR left ventricles. CONCLUSIONS: These results demonstrate alterations in multiple pathways associated with ß-adrenergic signaling and sarcolipin in the left ventricles of patients with isolated MR and LV ejection fraction>50%, suggesting a beneficial role for ß-adrenergic blockade in isolated MR.


Subject(s)
Adrenergic Agents/metabolism , Mitral Valve Insufficiency/metabolism , Muscle Proteins/metabolism , Proteolipids/metabolism , Stroke Volume/physiology , Ventricular Dysfunction, Left/metabolism , Adult , Aged , Biopsy , Case-Control Studies , Female , Gene Expression Profiling , Heart Ventricles/metabolism , Heart Ventricles/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Mitral Valve Insufficiency/physiopathology , Muscle Proteins/genetics , Proteolipids/genetics , Signal Transduction/physiology , Up-Regulation , Ventricular Dysfunction, Left/physiopathology
3.
Am J Physiol Heart Circ Physiol ; 305(10): H1440-50, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24014679

ABSTRACT

Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF ± allopurinol (100 mg·kg(-1)·day(-1), n ≥7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension (P < 0.001), a twofold increase in LV end-diastolic pressure/wall stress (P < 0.05), and a twofold increase in lung weight (P < 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF + allopurinol rats, all of which occurred in the absence of changes in the maximum O2 consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca(2+) sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure.


Subject(s)
Allopurinol/pharmacology , Cardiotonic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Heart Failure/drug therapy , Heart Ventricles/drug effects , Myocytes, Cardiac/drug effects , Systole/drug effects , Ventricular Function, Left/drug effects , Xanthine Oxidase/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Animals , Calcium Signaling/drug effects , Creatine Kinase/metabolism , Diastole/drug effects , Disease Models, Animal , Energy Metabolism/drug effects , Heart Failure/enzymology , Heart Failure/etiology , Heart Failure/physiopathology , Heart Ventricles/diagnostic imaging , Heart Ventricles/enzymology , Heart Ventricles/physiopathology , Hemodynamics/drug effects , Myocytes, Cardiac/enzymology , Oxygen Consumption/drug effects , Rats , Rats, Sprague-Dawley , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/enzymology , Stroke Volume/drug effects , Time Factors , Ultrasonography , Ventricular Pressure/drug effects , Xanthine Oxidase/metabolism
4.
Psychopharmacology (Berl) ; 228(4): 551-61, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23732837

ABSTRACT

RATIONALE: Methamphetamine (METH) induces hyperthermia in warm and hypothermia in cool environments. Our first goal was to further study the role of ambient temperature in METH's effect on core temperature in rats. Previously, these effects were primarily demonstrated in high doses; we extended this investigation to the low-dose range (1 mg/kg METH). Our second goal was to identify the role of the D2 receptor in METH's effects in cool ambient temperatures. METHOD: Rats received METH (saline, 1, 5, and 10 mg/kg), raclopride (saline, 0.3, 0.6, and 1.2 mg/kg), or a combination (all doses of raclopride combined with 10 mg/kg METH). Treatments occurred in ambient temperatures of 18, 24, or 30 °C. RESULTS AND CONCLUSIONS: Consistent with prior research, 5 and 10 mg/kg METH caused hyperthermia or hypothermia in a dose- and ambient temperature-dependent manner (60 min after METH). In contrast, 1 mg/kg produced similar levels of hyperthermia at all ambient temperatures. These findings suggest that a threshold METH dose exists; below this dose, METH still changes core temperature, but CNS control over temperature regulation is left intact. In our experiments regarding D2 blockade, raclopride decreased METH-induced core temperature at 30 and 24 °C (60 min after METH), consistent with previous findings. We extended these findings by demonstrating that in a cool ambient temperature (18 °C), raclopride pretreatment also lowered the core temperature response to METH. Although the D2 receptor is known to mediate hypothermia, the combination of METH and D2 blockade suggests a complex mediation of the core temperature response, perhaps involving neurotransmitter interactions.


Subject(s)
Fever/chemically induced , Hypothermia/chemically induced , Methamphetamine/pharmacology , Raclopride/pharmacology , Animals , Body Temperature/drug effects , Dopamine Agents/administration & dosage , Dopamine Agents/pharmacology , Dopamine Antagonists/administration & dosage , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Male , Methamphetamine/administration & dosage , Raclopride/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Temperature
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