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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
pPKCα mediated-HIF-1α activation related to the morphological modifications occurring in neonatal myocardial tissue
1Section of Human Anatomy, Faculty of Pharmacy, University G. d’Annunzio Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy. s.zara@unich.it
Insights
High oxygen exposure in newborn rats triggers heart injury via a PKC-mediated HIF-1α pathway, impacting blood vessel growth and apoptosis due to immature antioxidant defenses.
Area of Science:
- Cardiovascular Physiology
- Neonatal Medicine
- Molecular Biology
Background:
- Neonatal hyperoxia can impair myocardial function due to free radical release, contrasting with protective effects in adult animals.
- Age-dependent differences exist in the mechanisms and consequences of hyperoxia exposure on the heart.
Purpose of the Study:
- To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in hyperoxia-induced morphological changes in neonatal rat hearts.
- To explore the signaling pathways, including PKC and NOS, involved in neonatal hyperoxia response.
Main Methods:
- Exposure of neonatal rats to 95% oxygen.
- Analysis of HIF-1α translocation and VEGF expression.
- Assessment of PKC-α, e-NOS, and i-NOS expression.
- Evaluation of apoptotic events using TUNEL and Bax expression.
Main Results:
- Hyperoxia increased connective tissue and blood vessel growth, associated with elevated HIF-1α and VEGF.
- PKC-α expression increased, suggesting its involvement in HIF-1α activation.
- e-NOS expression decreased, while i-NOS expression increased, correlating with vasoconstriction and apoptosis.
- Apoptotic events were more pronounced under severe hyperoxia.
Conclusions:
- Neonatal hyperoxia can induce free radical-mediated injury via a PKCα-mediated HIF-1α signaling system.
- This pathway influences both blood vessel development and pro-apoptotic events in immature hearts.
- Specific inhibitors of PKCα may offer targeted interventions for hyperoxia-induced damage.
Abstract:
In premature babies birth an high oxygen level exposure can occur and newborn hyperoxia exposure can be associated with free radical oxygen release with impairment of myocardial function, while in adult animal models short exposure to hyperoxia seems to protect heart against ischemic injury. Thus, the mechanisms and consequences which take place after hyperoxia exposure are different and related to animals age. The aim of our work has been to analyze the role played by HIF-1α in the occurrence of the morphological modifications upon hyperoxia exposure in neonatal rat heart. Hyperoxia exposure induces connective compartment increase which seems to allow enhanced blood vessels growth. An increased hypoxia inducible factor-1α (HIF-1α) translocation and vascular endothelial growth factor (VEGF) expression has been found upon 95% oxygen exposure to induce morphological modifications. Upstream pPKC-α expression increase in newborn rats exposed to 95% oxygen can suggest PKC involvement in HIF-1α activation. Since nitric oxide synthase (NOS) are involved in heart vascular regulation, endothelial NOS (e-NOS) and inducible NOS (i-NOS) expression has been investigated: a lower eNOS and an higher iNOS expression has been found in newborn rats exposed to 95% oxygen related to the evidence that hyperoxia provokes a systemic vasoconstriction and to the iNOS pro-apoptotic action, respectively. The occurrence of apoptotic events, evaluated by TUNEL and Bax expression analyses, seems more evident in sample exposed to severe hyperoxia. All in all such results suggest that in newborn rats hyperoxia can trigger oxygen free radical mediated membrane injury through a pPKCα mediated HIF-1α signalling system, even though specificity of such response could be obtained by in vivo administration to the rats of specific inhibitors of PKCα. This intracellular signalling can switch molecular events leading to blood vessels development in parallel to pro-apoptotic events due to an immature anti-oxidant defensive system in newborn rat hearts.
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