Ioana Preston - Academia.edu (original) (raw)

Papers by Ioana Preston

Effects of hypoxia on rat airway smooth muscle cell proliferation. it is well known that hypoxemi... more Effects of hypoxia on rat airway smooth muscle cell proliferation. it is well known that hypoxemia induces pulmonary vasoconstriction and vascular remodeling, due to the proliferation of both vascular smooth muscle cells and fibroblasts, the effects of hypoxemia on airway smooth muscle cells are not well characterized. The present study was designed to assess the in vitro effects of hypoxia (1 or 3% O2) on rat airway smooth muscle cell growth and response to mitogens (PDGF and 5-HT). Cell growth was assessed by cell counting and cell cycle analysis. Compared with normoxia (21% O2), there was a 42.2% increase in the rate of proliferation of cells exposed to 3% O2 (72 h, P ϭ 0.006), as well as an enhanced response to PDGF (13.9% increase; P ϭ 0.023) and to 5-HT (17.2% increase; P ϭ 0.039). Exposure to 1% O2 (72 h) decreased cell proliferation by 21.0% (P ϭ 0.017) and reduced the increase in cell proliferation induced by PGDF and 5-HT by 16.2 and 15.7%, respectively (P ϭ 0.019 and P ϭ 0.011). A significant inhibition in hypoxia-induced cell proliferation was observed after the administration of bisindolylmaleimide GF-109203X (a specific PKC inhibitor) or downregulation of PKC with PMA. Pretreatment with GF-109203X decreased proliferation by 21.5% (P ϭ 0.004) and PMA by 31.5% (P ϭ 0.005). These results show that hypoxia induces airway smooth muscle cell proliferation, which is at least partially dependent on PKC activation. They suggest that hypoxia could contribute to airway remodeling in patients suffering from chronic, severe respiratory diseases. hypoxemia; protein kinase C; cell cycle; in vitro; cell growth

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and met... more The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previous ly studied. We sought evidence for a role of 12-LO and 12-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small size pulmonary arteries, and in alveolar walls of hypoxic lungs. 12-LO protein exp ression is increased in hypoxic cultured rat pulmonary artery SMCs. 12-HETE at concentrations as low as 10 -5 µM stimulated proliferation of pulmonary artery SMCs. 12-HETE induced ERK 1/ERK 2 phosphorylation, but had no effect on p38 kinase expression as assessed by Western blotting.

Expert review of respiratory medicine, 2015

Conducting clinical trials on pulmonary hypertension in the US and Western Europe has become incr... more Conducting clinical trials on pulmonary hypertension in the US and Western Europe has become increasingly difficult and costly because of many challenges. These include a limited patient population that makes recruitment difficult. Recruiting internationally has helped, but can add variability. The choice of end points is important but ideal end points that reflect pathogenesis of the disease are not available. The 6-min walk distance has been used in most trials to date, but recent trials have used an 'event-driven' design, in which combined outcomes are used to reflect progression of the disease. This design has advantages but requires many hundreds of patients and may take up to several years. Thus, there is still a role for functional or hemodynamic end points to enable testing of more new agents. Assuring the safety and scientific integrity of clinical trials without excessive regulation will also help facilitate the evaluation of additional therapies for this devastati...

JACC. Heart failure, 2015

The purpose of this study was to determine the predictors of mortality in patients with pulmonary... more The purpose of this study was to determine the predictors of mortality in patients with pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). PH is commonly associated with HFpEF. The predictors of mortality for patients with these conditions are not well characterized. In a prospective cohort of patients with right heart catheterization, we identified 73 adult patients who had pulmonary hypertension due to left heart disease (PH-LHD) associated with HFpEF (left ventricular ejection fraction ≥50% by echocardiography); hemodynamically defined as a mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure >15 mm Hg. PH severity was classified according to the diastolic pressure gradient (DPG). Cox proportional hazards ratios were used to estimate the associations between clinical variables and mortality. Receiver-operating characteristic curves were used to evaluate the ability of hemodynamic measurements to predict m...

Respiratory care, 2015

The inhaled route has a number of attractive features for treatment of pulmonary hypertension, in... more The inhaled route has a number of attractive features for treatment of pulmonary hypertension, including delivery of drug directly to the target organ, thus enhancing pulmonary specificity and reducing systemic adverse effects. It can also improve ventilation/perfusion matching by dilating vessels supplying ventilated regions, thus improving gas exchange. Furthermore, it can achieve higher local drug concentrations at a lower overall dose, potentially reducing drug cost. Accordingly, a number of inhaled agents have been developed to treat pulmonary hypertension. Most in current use are prostacyclins, including epoprostenol, which has been cleared for intravenous applications but is used off-label in acute care settings as a continuously nebulized medication. Aerosolized iloprost and treprostinil are both prostacyclins that have been cleared by the FDA to treat pulmonary arterial hypertension (PAH). Both require frequent administration (6 and 4 times daily, respectively), and both ha...

Annals of the American Thoracic Society, 2015

F1000 - Post-publication peer review of the biomedical literature, 2013

Developments in Cardiovascular Medicine, 2004

... Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou, Ioana R. Preston, and Nicholas S. Hill Wy... more ... Mallik R. Karamsetty, James C. Leiter, Lo Chang Ou, Ioana R. Preston, and Nicholas S. Hill Wyeth Pharmaceuticals, Richmond, Virginia; Dartmouth Medical ... Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I, and Busse R. Cytochrome P450 2C is an EDHF synthase ...

Postgraduate medicine, 2002

Experimental biology and medicine (Maywood, N.J.), 2004

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase sti... more We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were expose...

Proceedings of the American Thoracic Society, Jan 15, 2008

Results from clinical trials serve as the basis for approval of therapies by regulatory agencies ... more Results from clinical trials serve as the basis for approval of therapies by regulatory agencies as well as for treatment decisions by clinicians. But these findings are relevant only to patients who are similar to the ones enrolled into the trials. This is germane to clinical trials on pulmonary arterial hypertension (PAH) because the disease is uncommon but highly heterogeneous and results can easily be misapplied. The characteristics of patients entering the trials are largely determined by inclusion/exclusion criteria, with the result that most participants have idiopathic, connective tissue disease- and congenital heart disease-related PAH. Earlier trials enrolled patients mainly with New York Heart Association functional class III and IV disease and with severe pulmonary hemodynamic abnormalities. Because it has been the major outcome variable in most of the trials, eligibility is also dependent on six-minute-walk distance, ensuring that patients are moderately but not too sev...

Textbook of Pulmonary Vascular Disease, 2010

Individual pharmacotherapies for pulmonary arterial hypertension (PAH) have significantly improv... more Individual pharmacotherapies for pulmonary arterial hypertension (PAH) have significantly improved functional status, quality of life, and, in the case of epoprostenol (Epo), survival of PAH patients with the idiopathic form (IPAH), but these responses are usually partial and often temporary. In addition, these agents have potential adverse side effects and risks that may be dose-related. These limitations have stimulated interest

European respiratory review : an official journal of the European Respiratory Society, 2013

The past two decades have seen significant improvements in the management of patients with pulmon... more The past two decades have seen significant improvements in the management of patients with pulmonary arterial hypertension (PAH). Although outcome has improved, long-term prognosis remains unsatisfactory. The development of new treatment options is clearly important. Equally important is testing new agents in trials designed to provide robust evidence for sustained clinical benefits enabling clinicians to determine the optimal treatment strategy for individual patients. End-points such as the change in 6-min walk distance (6MWD) have been pivotal in the registration trials of currently available PAH-specific therapies. However, as current clinical trials enrol patients with milder disease, many already on background therapy, there is growing evidence that change from baseline in 6MWD is a weak surrogate of outcome in PAH. In addition, while short-term trials allowed for the rapid approval of PAH therapies in the past, there is increasing recognition that clinical trials for new agen...

F1000 - Post-publication peer review of the biomedical literature, 2000

Cellular Signalling, 2014

Tissue transglutaminase 2 (TG2) is a multifunctional enzyme that cross-links proteins with monoam... more Tissue transglutaminase 2 (TG2) is a multifunctional enzyme that cross-links proteins with monoamines such as serotonin (5-hydroxytryptamine, 5-HT) via a transglutamidation reaction, and is associated with pathophysiologic vascular responses. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PASMCs) that has been linked to pulmonary vascular remodeling underlying pulmonary hypertension development. We previously reported that 5-HT-induced PASMC proliferation is inhibited by the TG2 inhibitor monodansylcadaverine (MDC); however, the mechanisms are poorly understood. In the present study we hypothesized that TG2 contributes to 5-HT-induced signaling pathways of PASMCs. Pre-treatment of bovine distal PASMCs with varying concentrations of the inhibitor MDC led to differential inhibition of 5-HT-stimulated AKT and ROCK activation, while p-P38 was unaffected. Concentration response studies showed significant inhibition of AKT activation at 50 μM MDC, along with inhibition of the AKT downstream targets mTOR, p-S6 kinase and p-S6. Furthermore, TG2 depletion by siRNA led to reduced 5-HT-induced AKT activation. Immunoprecipitation studies showed that 5-HT treatment led to increased levels of serotonylated AKT and increased TG2-AKT complex formations which were inhibited by MDC. Overexpression of TG2 point mutant cDNAs in PASMCs showed that the TG2 C277V transamidation mutant blunted 5-HT-induced AKT activation and 5-HT-induced PASMC mitogenesis. Finally, 5-HT-induced AKT activation was blunted in SERT genetic knock-out rat cells, but not in their wild-type counterpart. The SERT inhibitor imipramine similarly blocked AKT activation. These results indicate that TG2 contributes to 5-HT-induced distal PASMC proliferation via promotion of AKT signaling, likely via its serotonylation. Taken together, these results provide new insight into how TG2 may participate in vascular smooth muscle remodeling.

B59. PULMONARY ARTERIAL HYPERTENSION: DIAGNOSIS, HEMODYNAMIC ASSESSMENT, AND IMAGING, 2010

Inhaled nitric oxide (iNO) is used for acute vasoreactivity testing in pulmonary arterial hyperte... more Inhaled nitric oxide (iNO) is used for acute vasoreactivity testing in pulmonary arterial hypertension (PAH) patients. Inhaled epoprostenol (iPGI 2 ) has pulmonary selectivity and is less costly. We sought to compare acute hemodynamic effects of iNO (20 ppm) and iPGI 2 (50 ng/kg/min) and determine whether their combination has additive effects. We conducted a prospective, single center, randomized, cross-over study in 12 patients with PAH and seven with heart failure with preserved ejection fraction (HFpEF). In PAH patients, iNO lowered mean pulmonary artery pressure (mPAP) by 9 ± 12% and pulmonary vascular resistance (PVR) by 14 ± 32% (mean ± SD). iPGI 2 decreased mPAP by 10 ± 12% and PVR by 12 ± 36%. Responses to iNO and iPGI 2 in mPAP and PVR were directly correlated (r 2 = 0.68, 0.70, respectively, P < 0.001). In HFpEF patients, mPAP dropped by 4 ± 7% with each agent, and PVR dropped by 33 ± 23% with iNO, and by 25 ± 29% with iPGI 2 (P = NS). Pulmonary artery wedge pressure (PAWP) increased significantly with iPGI 2 versus baseline (20 ± 3 vs. 17 ± 2 mmHg, P = 0.02) and trended toward an increase with iNO and the combination (20 ± 2, 19 ± 4 mmHg, respectively). There were no additive effects in either group. In PAH patients, the vasodilator effects of iNO and iPGI 2 correlated at the doses used, making iPGI 2 a possible alternative for testing acute vasoreactivity, but their combination lacks additive effect. Exposure of HFpEF patients to inhaled vasodilators worsens the PAWP without hemodynamic benefit.

Postgraduate Medicine, 2002

Postgraduate Medicine, 2001