Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

Milano, Giuseppina; Abruzzo, Provvidenza Maria; Bolotta, Alessandra; Marini, Marina; Terraneo, Laura; Ravara, Barbara; Gorza, Luisa; Vitadello, Maurizio; Burattini, Sabrina; Curzi, Davide; Falcieri, Elisabetta; Segesser, Ludwig K. von; Samaja, Michele

doi:10.1371/journal.pone.0076659

Cited by 24 publications

(20 citation statements)

References 64 publications

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“…Lungs were quickly rinsed in ice‐cold PBS (pH 7.4) and clamped between steel tongs pre‐cooled with liquid N 2 and stored at ‐80°C until analysis. For Western blotting analyses, frozen lung tissues were homogenized in lysis buffer plus protease inhibitor cocktail (Santa Cruz Biotechnology) and processed as described elsewhere , using the following primary antibodies: anti‐p‐eNOS (Ser 1177 , Cell Signalling Technology), anti‐eNOS (Santa Cruz Biotechnology), anti‐p‐Akt (Ser 473 ) and anti‐Akt (both Cell Signaling Technologies). Band intensities were quantified using ImageJ software.…”

Section: Methodsmentioning

confidence: 99%

Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells

Favre¹,

Gambini

Nigro

et al. 2016

J Cellular Molecular Medi

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The recruitment of bone marrow (BM)‐derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM‐derived progenitor cells, we induced pulmonary remodelling in rats by two‐week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM‐derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH‐induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH‐induced increase in c‐kit+ cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c‐kit+ cells that colocalize with tyrosine kinase receptor 2 (VEGF‐R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia‐induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia‐inducible factor (HIF)‐1α. Furthermore, sildenafil depressed the number of CXCR4+ cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM‐derived c‐kit+ cells in the pulmonary tissue. The attenuation of the recruitment of BM‐derived c‐kit+ cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.

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Section: Methodsmentioning

confidence: 99%

Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells

Favre¹,

Gambini

Nigro

et al. 2016

J Cellular Molecular Medi

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“…In contrast, IH has also been proposed as a technique to improve physiological performance based on the phenomenon of adaptation to reduced oxygen, similar to mechanisms observed with ischemia-reperfusion preconditioning. IH has been shown to improve endothelial function in hypertension [ 18 ] and to limit infarct size [ 19 ]. The opposite outcomes observed in studies using IH can be influenced by the diversity and duration of IH patterns applied.…”

Section: Introductionmentioning

confidence: 99%

Vascular and Hepatic Impact of Short-Term Intermittent Hypoxia in a Mouse Model of Metabolic Syndrome

et al. 2015

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BackgroundExperimental models of intermittent hypoxia (IH) have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS).MethodsMice were fed either a standard diet or a high fat diet (HFD) for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day) or intermittent air (FiO2 21%). Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO) release.ResultsMice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH) activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.ConclusionIn a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

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“…Indeed, studies in the heart have indicated that the duration of CIH exposure can determine the outcome of myocardial ischemia 14-16 , an effect in part related to changes in the susceptibility of mitochondria to damage 17,18 . However, it is unclear how the duration of CIH and the intensity of the episodic hypoxia influence the outcome of cerebral ischemia and whether mitochondria may play a role in determining the fate of the ischemic tissue.…”

Section: Introductionmentioning

confidence: 99%

Dichotomous Effects of Chronic Intermittent Hypoxia on Focal Cerebral Ischemic Injury

Jackman

Zhou

Faraco

et al. 2014

Stroke

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Background and purpose Obstructive sleep apnea (OSA), a condition associated with chronic intermittent hypoxia (CIH), carries an increased risk of stroke. However, CIH has been reported to either increase or decrease brain injury in models of focal cerebral ischemia. The factors determining the differential effects of CIH on ischemic injury and their mechanisms remain unclear. Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury. Methods Male C57Bl/6J mice were exposed to CIH with 10% or 6% O2 for up to 35 days and subjected to transient middle cerebral artery occlusion (MCAO). Motor deficits and infarct volume were assessed 3 days later. Intra-ischemic CBF was measured by laser-Doppler flowmetry and resting CBF by arterial spin labeling MRI. Ca2+-induced mitochondrial depolarization and reactive oxygen species (ROS) production were evaluated in isolated brain mitochondria. Results We found that 10% CIH is neuroprotective, while 6% CIH exacerbates tissue damage. No differences in resting or intra-ischemic CBF were observed between 6% and 10% CIH. However, 10% CIH reduced, while 6% CIH increases mitochondrial ROS production and susceptibility to Ca2+-induced depolarizations. Conclusions The influence of CIH on the ischemic brain is dichotomous and can be attributed in part to changes in the mitochondrial susceptibility to injury. The findings highlight a previously unappreciated complexity in the effect of CIH on the brain, which needs to be considered in evaluating the neurological impact of conditions associated with cyclic hypoxia.

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Impact of the Phosphatidylinositide 3-Kinase Signaling Pathway on the Cardioprotection Induced by Intermittent Hypoxia

Cited by 24 publications

References 64 publications

Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells

Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells

Vascular and Hepatic Impact of Short-Term Intermittent Hypoxia in a Mouse Model of Metabolic Syndrome

Dichotomous Effects of Chronic Intermittent Hypoxia on Focal Cerebral Ischemic Injury

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