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Biomedical subjects

Steven P Jones

Publications and source records attributed to Steven P Jones.

16 recordsLinked to original sources
PubMed2006

Low-dose simvastatin improves survival and ventricular function via eNOS in congestive heart failure.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase endothelial nitric oxide synthase (eNOS) activity by multiple mechanisms. We previously reported that genetic overexpression of eNOS improves survival and cardiac function in congestive heart failure (CHF). In the present study, we tested the hypothesis that low-dose treatment with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor exerts beneficial effects on survival and/or cardiac function in a murine model of CHF. Mice were subjected to permanent ligation of the left coronary artery and randomized to receive either saline vehicle or simvastatin (0.25 mg/kg) 2 h after myocardial infarction and daily (0.25 mg/kg) for 7 days, followed by 21 days of administration every other day for a total duration of 28 days. Myocardial infarct size was not reduced by simvastatin therapy (P = not significant between groups). Simvastatin treatment did significantly (P < 0.05) improve survival (45%) compared with vehicle treatment (25%). In addition, simvastatin treatment significantly improved (P < 0.01) left ventricular function and significantly (P < 0.01) abrogated cardiac hypertrophy and pulmonary edema compared with vehicle treatment. The protective effects of simvastatin were abrogated by delayed initiation of treatment or genetic ablation of eNOS. In conclusion, low-dose simvastatin therapy significantly improves survival and cardiac function and reduces both cardiac hypertrophy and pulmonary edema via an eNOS-dependent mechanism in a murine model of CHF.

Animals↗
PubMed2005

The ubiquitous role of nitric oxide in cardioprotection.

In recent years, major advances have been made toward understanding the role of nitric oxide (NO) in the ischemic biology of the heart. It is now clear that NO, either endogenous or exogenous, represents one of the most important defenses against myocardial ischemia-reperfusion injury. The purpose of this review is to provide an update on the cardioprotective actions of NO, with particular emphasis on the function of the inducible isoform of NO synthase (iNOS) and on the role of mitochondria in NO-mediated protection. This essay underscores some of the more prominent areas of ischemic biology that relate to NO, such as ischemic preconditioning, pharmacological cardioprotection, and gene therapy. The hypothesis that the late phase of preconditioning is mediated by increased iNOS activity resulting in enhanced NO bioavailability, first proposed by our group, is now widely accepted and can be regarded as a proven hypothesis. Likewise, the burgeoning field of postconditioning may share such a requirement for NO. Various drugs (e.g. statins, ACE inhibitors, angiotensin-receptor blockers, etc.) also produce salubrious effects in experimental models of myocardial infarction via their enhancement of NO bioavailability. Thus, NO appears to be a common mediator of the protection afforded by a wide array of seemingly unrelated pharmacological and nonpharmacological interventions, underscoring its fundamental role as a ubiquitous defense of the heart against ischemia and reperfusion. This review challenges the conventional wisdom that iNOS is deleterious during myocardial ischemia-reperfusion and instead proposes the concept that iNOS, when expressed in cardiac myocytes, is a profoundly protective protein. We also emphasize the emerging importance of the mitochondrial actions of NO. Although the precise molecular events remain to be defined, we propose that NO interacts with components of the electron transport chain and/or the mitochondrial permeability transition pore to limit post-ischemic myocardial damage, and that this action potentially provides a fundamental molecular explanation for the mechanism of NO-mediated cardioprotection.

Animals↗
PubMed2004

Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers.

BACKGROUND: Human embryonic stem cells (hESCs) derived from blastocysts can propagate indefinitely in culture while maintaining pluripotency, including the ability to differentiate into cardiomyocytes (CMs); therefore, hESCs may provide an unlimited source of human CMs for cell-based therapies. Although CMs can be derived from hESCs ex vivo, it remains uncertain whether a functional syncytium can be formed between donor and recipient cells after engraftment. METHODS AND RESULTS: Using a combination of electrophysiological and imaging techniques, here we demonstrate that electrically active, donor CMs derived from hESCs that had been stably genetically engineered by a recombinant lentivirus can functionally integrate with otherwise-quiescent, recipient, ventricular CMs to induce rhythmic electrical and contractile activities in vitro. The integrated syncytium was responsive to the beta-adrenergic agonist isoproterenol as well as to other pharmacological agents such as lidocaine and ZD7288. Similarly, a functional hESC-derived pacemaker could be implanted in the left ventricle in vivo. Detailed optical mapping of the epicardial surface of guinea pig hearts transplanted with hESC-derived CMs confirmed the successful spread of membrane depolarization from the site of injection to the surrounding myocardium. CONCLUSIONS: We conclude that electrically active, hESC-derived CMs are capable of actively pacing quiescent, recipient, ventricular CMs in vitro and ventricular myocardium in vivo. Our results may lead to an alternative or a supplemental method for correcting defects in cardiac impulse generation, such as cell-based pacemakers.

Action Potentials↗
PubMed2004

Deficiency of iNOS does not attenuate severe congestive heart failure in mice.

Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS(-/-)) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type (n = 17), sham iNOS(-/-) (n = 8), MI wild-type (n = 56), and MI iNOS(-/-) (n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 +/- 2.0% and 441 +/- 20 microl.min(-1).g(-1)) and iNOS(-/-) (9.8 +/- 1.3% and 471 +/- 26 microl.min(-1).g(-1)) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS(-/-) mice. None of the indexes demonstrated any significant differences between iNOS(-/-) and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.

Animals↗
PubMed2003

Cariporide (HOE642), a selective Na+-H+ exchange inhibitor, inhibits the mitochondrial death pathway.

BACKGROUND: The Na+-H+ exchanger figures prominently in cardiac ischemia-reperfusion injury. Several experimental and clinical studies have demonstrated a cardioprotective effect of Na+-H+ exchanger inhibition; however, the precise mechanisms have not been established. METHODS AND RESULTS: We examined the effects of cariporide (HOE642, 10 micromol/L) on cell death induced by oxidative stress (H2O2, 100 micromol/L) in cultured neonatal rat cardiomyocytes. Cariporide significantly suppressed markers of cell death, such as TUNEL positivity and caspase-3 cleavage, at 8 or 16 hours after H2O2. The early phase of cell death, reported by increases in phosphatidylserine exposure and propidium iodide uptake, was also inhibited by cariporide. To explore the mechanisms of cell protection, we examined the effects of cariporide on increases in intracellular Na+ and Ca2+ induced by oxidative stress. Cariporide remarkably suppressed cytosolic Na+ and Ca2+ accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca2+ overload induced by H2O2 was remarkably suppressed by cariporide. Loss of mitochondrial membrane potential is a critical step of the death pathway; cariporide prevented mitochondrial membrane potential loss induced by H2O2. CONCLUSIONS: Cariporide protects cardiomyocytes against oxidant-induced cell death by preserving intracellular ion homeostasis and mitochondrial integrity.

Animals↗
PubMed2003

Simvastatin attenuates oxidant-induced mitochondrial dysfunction in cardiac myocytes.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can exert beneficial effects independently of serum cholesterol reduction by increasing the bioavailability of nitric oxide. However, it is unclear whether statins can exert such effects directly on cardiac myocytes and whether mitochondria are potential targets. Neonatal rat cardiac myocytes were cultured and subjected to oxidant stress (1 hour of 100 micromol/L H2O2). Mitochondrial membrane potential, a key determinant of cardiomyocyte viability, was assessed by flow cytometric analysis of tetramethylrhodamine ethyl ester (TMRE)-loaded cells. Hydrogen peroxide significantly reduced mitochondrial membrane potential. Incubation of the cardiac myocytes in simvastatin (> or =1 micromol/L) 1 hour before peroxide exposure significantly attenuated the loss of TMRE fluorescence. This effect was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the ATP-sensitive mitochondrial potassium channel (mitoKATP) blocker 5-hydroxydecanoate. Simvastatin attenuates mitochondrial membrane depolarization after exposure to oxidant stress. These findings provide primary evidence that myocytes can act as triggers and effectors in the cardioprotective cascade of simvastatin therapy. These results bear implications of statin therapy as a potential clinical application of pharmacological preconditioning.

Animals↗
PubMed2003

Endothelial nitric oxide synthase overexpression attenuates myocardial reperfusion injury.

Previous studies indicate that deficiency of endothelial nitric oxide (NO) synthase (eNOS)-derived NO exacerbates myocardial reperfusion injury. We hypothesized that overexpression of eNOS would reduce the extent of myocardial ischemia-reperfusion (MI/R) injury. We investigated two distinct strains of transgenic (TG) mice overexpressing the eNOS gene (eNOS TG). Bovine eNOS was overexpressed in one strain (eNOS TG-Kobe), whereas the human eNOS gene was overexpressed in the other strain (eNOS TG-RT). Non-TG (NTG) and eNOS TG mice were subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion, and the extent of myocardial infarction was determined. Myocardial infarct size was reduced by 33% in the eNOS TG-Kobe strain (P < 0.05 vs. NTG) and by 32% in the eNOS TG-RT strain (P < 0.05 vs. NTG). However, postischemic cardiac function (cardiac output, fractional shortening) was not improved in the eNOS TG-Kobe mouse at 24 h of reperfusion [P = not significant (NS) vs. NTG]. In additional studies, eNOS TG-Kobe mice were subjected to 30 min of myocardial infarction and 7 days of reperfusion. Fractional shortening and the first derivative of left ventricular pressure were measured in eNOS TG-Kobe and NTG mice, and no significant differences in contractility were observed (P = NS) between the eNOS TG mice and NTG controls. Left ventricular end-diastolic pressure was significantly (P < 0.05 vs. NTG) reduced in the eNOS TG-Kobe strain at 7 days of reperfusion. The cardioprotective effects of eNOS overexpression on myocardial infarct size were ablated by Nomega-nitro-l-arginine methyl ester (300 mg/kg) pretreatment. Thus genetic overexpression of eNOS in mice attenuates myocardial infarction after MI/R but fails to significantly protect against postischemic myocardial contractile dysfunction in mice.

Alkenes↗
PubMed2003

Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes.

Uncoupling proteins (UCPs) are located in the mitochondrial inner membrane and partially dissipate the transmembrane proton electrochemical gradient. UCP2 is expressed in various human and rodent tissues, including the heart, where its functional role is unknown. In the present study, we tested the hypothesis that UCP2 overexpression could protect cardiomyocytes from oxidative stress-induced cell death by reducing reactive oxygen species (ROS) production in mitochondria. Using an adenoviral vector containing human UCP2, we investigated the effects of UCP2 overexpression on the mitochondrial death pathway induced by oxidative stress (100 micromol/L H2O2) in cultured neonatal cardiomyocytes. UCP2 overexpression significantly suppressed markers of cell death, including TUNEL positivity, phosphatidylserine exposure, propidium iodide uptake, and caspase-3 cleavage. Furthermore, UCP2 remarkably prevented the catastrophic loss of mitochondrial inner membrane potential induced by H2O2, which is a critical early event in cell death. Ca2+ overload and the production of ROS in mitochondria, both of which contribute to mitochondrial inner membrane potential loss, were dramatically attenuated by UCP2 overexpression. Thus, overexpression of UCP2 attenuates ROS generation and prevents mitochondrial Ca2+ overload, revealing a novel mechanism of cardioprotection.

Adenoviridae↗
PubMed2003

Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice.

Congestive heart failure results in cardiovascular dysfunction and diminished vascular nitric oxide (NO) production. We hypothesized that overexpression of endothelial NO synthase (eNOS) within the endothelium would reduce the extent of contractile dysfunction in a murine model of infarct-induced congestive heart failure. We generated transgenic (TG) mice overexpressing the human eNOS gene. The TG mice displayed significantly enhanced eNOS protein levels and eNOS activity levels (10- to 12-fold greater) in the aorta and the coronary vasculature. Non-TG (NTg) and eNOS TG mice were subjected to permanent left anterior descending coronary artery occlusion and then observed for 1 mo. We assessed cardiac function in vivo by using echocardiography and ultraminiature ventricular pressure catheters. Myocardial infarct size was similar between study groups (approximately 70% of the risk zone). Survival was increased by 43% in the eNOS TG mice compared with NTg (P < 0.05). Fractional shortening and cardiac output were also significantly (P < 0.05) greater in the eNOS TG than in NTg. Interestingly, pulmonary edema was evident only in NTg mice, and no evidence of pulmonary edema was observed in the eNOS TG mice. Thus, targeted overexpression of the eNOS gene within the vascular endothelium in mice attenuates both cardiac and pulmonary dysfunction and dramatically improves survival during severe congestive heart failure.

Animals↗
PubMed2003

Endothelial cell overexpression of fas ligand attenuates ischemia-reperfusion injury in the heart.

Fas ligand (FasL) is a member of tumor necrosis factor family that induces apoptosis in target cells that express Fas. The function of FasL during inflammation remains controversial. In this study, we examined the role of vascular endothelial FasL during acute myocardial ischemia-reperfusion that is closely associated with inflammation. Transgenic mouse lines were established that overexpress human FasL on endothelium under the control of the vascular endothelial cadherin promoter. Expression of FasL transgene was detected at both mRNA and protein levels, and functional transgene-encoded FasL protein was specifically expressed on the surface of vascular endothelial cells. Transgenic mice developed normally and had normal hearts. When subjected to 30 min of myocardial ischemia and 72 h of reperfusion, myocardial infarct size was reduced by 42% in the transgenic mice compared with nontransgenic littermates (p < 0.05). Moreover, hemodynamic data demonstrated that transgenic hearts performed better following ischemia and reperfusion compared with nontransgenic hearts. Myocardial neutrophil infiltration was reduced by 54% after 6 h of reperfusion in transgenic hearts (p < 0.01). Neutrophil depletion prior to ischemia-reperfusion injury led to smaller infarcts that were not different between transgenic and nontransgenic mice, suggesting that endothelial FasL may attenuate ischemia-reperfusion injury by abating the inflammatory response. These results indicate that vascular endothelial FasL may exert potent anti-inflammatory actions in the setting of myocardial ischemia-reperfusion injury.

Animals↗
PubMed2003

Differential actions of cardioprotective agents on the mitochondrial death pathway.

We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (DeltaPsi(m)) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved DeltaPsi(m), (2) depolarization, the rapid DeltaPsi(m) depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing DeltaPsi(m) depolarization but also delayed the onset of DeltaPsi(m) loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoK(ATP) channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for DeltaPsi(m) depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoK(ATP) channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.

Bongkrekic Acid↗
PubMed2003

Role of intracellular antioxidant enzymes after in vivo myocardial ischemia and reperfusion.

Reactive oxygen species induce myocardial damage after ischemia and reperfusion in experimental animal models. Numerous studies have investigated the deleterious effects of ischemia-reperfusion (I/R)-induced oxidant production using various pharmacological interventions. More recently, in vitro studies have incorporated gene-targeted mice to decipher the role of antioxidant enzymes in myocardial reperfusion injury. We examined the role of cellular antioxidant enzymes in the pathogenesis of myocardial I/R (MI/R) injury in vivo in gene-targeted mice. Neither deficiency nor overexpression of Cu-Zn superoxide dismutase (SOD) altered the extent of myocardial necrosis. Overexpression of glutathione peroxidase did not affect the degree of myocardial injury. Conversely, overexpression of manganese (Mn)SOD significantly attenuated myocardial necrosis after MI/R. Transthoracic echocardiography was performed on MnSOD-overexpressing and wild-type mice that were subjected to a more prolonged period of reperfusion. Cardiac output was significantly depressed in the nontransgenic but not the transgenic MnSOD-treated mice. Anterior wall motion was significantly impaired in the nontransgenic mice. These findings demonstrate an important role for MnSOD but not Cu/ZnSOD or glutathione peroxidase in mice after in vivo MI/R.

Animals↗
PubMed2002

Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor.

OBJECTIVE: We examined the possible effects of a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on endothelial nitric oxide (NO) production and myocardial ischemia-reperfusion injury. BACKGROUND: Recent studies suggest that HMG-CoA reductase inhibitors promote vascular endothelial function through enhanced endothelial NO production. However, it is unclear whether all statins share this beneficial side effect or whether this effect is limited to the "natural" statins. METHODS: Wild-type mice (n = 158) were subjected to 30 min of regional myocardial ischemia and 24 h of reperfusion. Mice were treated with various doses of rosuvastatin (0.1, 0.5, 1.0, 2.0, and 5.0 mg/kg) 18 h before myocardial ischemia and reperfusion. RESULTS: Rosuvastatin significantly increased NO production from the vascular endothelium following acute administration to mice. In addition, rosuvastatin increased myocardial endothelial nitric oxide synthase (eNOS) messenger ribonucleic acid levels. Myocardial necrosis was reduced by approximately 40% with rosuvastatin therapy. Rosuvastatin attenuated myocardial injury when it was administered 6 h, but not 0 h or 3 h, before myocardial ischemia. In additional studies, rosuvastatin did not affect myocardial infarct size in eNOS-deficient mice compared to vehicle-treated eNOS mice. CONCLUSION: These data demonstrate that rosuvastatin increases vascular endothelial NO production and attenuates myocardial necrosis following ischemia and reperfusion in mice.

Animals↗
PubMed2002

Differential response to myocardial reperfusion injury in eNOS-deficient mice.

Two strains of endothelial nitric oxide synthase (eNOS)-deficient (-/-) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS(-/-) mice in an in vivo model of MI/R. Harvard (Har) eNOS(-/-) mice (n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls (P < 0.05). University of North Carolina (UNC) eNOS(-/-) (n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls (P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant (P < 0.05) increase in the UNC eNOS(-/-) mice compared with wild-type mice, and there was no significant difference between the Har eNOS(-/-) and wild-type mice. UNC eNOS(-/-) mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS(-/-) did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS(-/-) mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS(-/-) mouse may result from compensatory increases in iNOS, other genes may be involved.

Animals↗
PubMed2002

Advances in orthodontics.

There has been tremendous progress in orthodontics since Edward Angle first popularised the fixed orthodontic appliance at the turn of the century. Recent years have seen an increased demand for orthodontic treatment from both adolescents and adults and, in addition, patient and clinician expectations of treatment outcomes continue to rise. A desire for more aesthetic materials has resulted in both smaller and 'tooth-coloured' appliances. Improvements in technology, often outside orthodontics, have also led to the development of new materials. The best example of this was the development of nickel titanium alloy by the NASA space programme, which was subsequently adapted for use in nickel titanium archwires. Other technological advances adopted for use in orthodontics include magnets, computerised imaging systems and distraction osteogenesis. This review paper looks at some of the innovations in the fields of materials as well as in techniques and appliance systems.

Adolescent↗