Abstract
The redox imbalance and the consequent oxidative stress have been implicated in many pathological conditions, including cardiovascular diseases. The lack or the excess of O2 supply can alter the redox balance. The aim of the present study was to understand the heart responses to prolonged hypoxia or hyperoxia and how such situations may activate survival mechanisms or trigger cell death. Seven-week-old Foxn1 mice were exposed to hypoxia (10% O2), normoxia (21% O2), or hyperoxia (30% O2) for 28 days, then the heart tissue was excised and analyzed. The alterations in redox balance, housekeeping protein levels, and autophagic and apoptotic process regulation were studied. The D-ROM test demonstrated an increased oxidative stress in the hypoxic group compared to the hyperoxic group. The level of hypoxia inducible factor-1 (HIF-1α) was increased by hypoxia while HIF-2α was not affected by treatments. Chronic hypoxia activated the biochemical markers of autophagy, and we observed elevated levels of Beclin-1 while LC3B-II and p62 were constant. Nevertheless, we measured significantly enhanced number of TUNEL-positive cells and higher Bax/Bcl2 ratio in hyperoxia with respect to hypoxia. Surprisingly, our results revealed alterations in the level of housekeeping proteins. The expression of α-tubulin, total-actin, and GAPDH was increased in the hypoxic group while decreased in the hyperoxic group. These findings suggest that autophagy is induced in the heart under hypoxia, which may serve as a protective mechanism in response to enhanced oxidative stress. While prolonged hypoxia-induced autophagy leads to reduced heart apoptosis, low autophagic level in hyperoxia failed to prevent the excessive DNA fragmentation.
Highlights
The mammal heart is an organ with relatively high demand for O2 and high O2 consumption; the O2 supply may often be insufficient with respect to needs due to limitations in O2 delivery, thereby establishing a condition of hypoxia that may frequently accompany cardiovascular disorders such as thrombosis, atherosclerosis, and pulmonary disorders [1]
The Tukey test did not show statistical differences between 21% O2 and 10% O2, as well as between 21% O2 and 30% O2, the linear regression analysis shows that the slope was significantly greater than zero, indicating that the body weight (BW) values were positively related to % O2
These proteins should be used with caution as loading controls, and the alternative method to normalize densitometry values against total protein content is to be taken into serious consideration
Summary
The mammal heart is an organ with relatively high demand for O2 and high O2 consumption; the O2 supply may often be insufficient with respect to needs due to limitations in O2 delivery, thereby establishing a condition of hypoxia that may frequently accompany cardiovascular disorders such as thrombosis, atherosclerosis, and pulmonary disorders [1]. Reactive oxygen species (ROS) are known to play crucial roles in the functional response of the myocardium to altered O2 levels [3], and their role has been extensively investigated [4]. The direction of the alteration is opposite to that elicited by the reverse condition, hypoxia. Such responses might be considered to have a relevant impact on the body’s adaptation to altered O2 consumption, which includes the regulation of gene transcription by the hypoxia-inducible factors (HIFs). HIFs act as transcriptional factors for an array of genes that participate in various cell processes such as angiogenesis, metabolism, cell proliferation, and control of ROS-induced damage [6], including
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