Mechanisms of Cardiovascular Protection Associated with Intermittent Hypobaric Hypoxia Exposure in a Rat Model: Role of Oxidative Stress

Abstract

More than 140 million people live and works (in a chronic or intermittent form) above 2500 m worldwide and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 55,000 persons work in high altitude shifts, where stays at lowlands and interspersed with working stays at highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders, due to an increase in free radical formation and a decrease in antioxidant capacity. However, in animal models, intermittent hypoxia (IH) induce preconditioning, like responses and cardioprotection. Here, we aimed to describe in a rat model the responses on cardiac and vascular function to 4 cycles of intermittent hypobaric hypoxia (IHH). Twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH, and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days hypoxia + 4 days normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the first and fourth cycle, cardiac structural, and functional variables were determined by echocardiography. Thereafter, ex vivo vascular function and biomechanical properties were determined in femoral arteries by wire myography. We further measured cardiac oxidative stress biomarkers (4-Hydroxy-nonenal, HNE; nytrotirosine, NT), reactive oxygen species (ROS) sources (NADPH and mitochondrial), and antioxidant enzymes activity (catalase, CAT; glutathione peroxidase, GPx, and superoxide dismutase, SOD). Our results show a higher ejection and shortening fraction of the left ventricle function by the end of the 4th cycle. Further, femoral vessels showed an improvement of vasodilator capacity and diminished stiffening. Cardiac tissue presented a higher expression of antioxidant enzymes and mitochondrial ROS formation in IHH, as compared with normobaric hypoxic controls. IHH exposure determines a preconditioning effect on the heart and femoral artery, both at structural and functional levels, associated with the induction of antioxidant defence mechanisms. However, mitochondrial ROS generation was increased in cardiac tissue. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

H2O2 Signaling‐Triggered PI3K Mediates Mitochondrial Protection to Participate in Early Cardioprotection by Exercise Preconditioning

“…In the present study, HBFP staining indicated that exhaustive exercise is associated with hypoxic-ischemic aggravation. However, exercise-induced acute redox unbalance has been also known to function as a key signaling pathway that provides cardioprotection [ 49 , 50 ]. We did not observe H 2 O 2 induction in the EE group, which might be related to the suppression in mitochondrial MnSOD and cellular T-SOD activities.…”

“…Therefore, the excessive production of ROS during EE will be scavenged by the enhanced SOD activities of EEP, thereby further forming H 2 O 2 during EEP + EE. A previous study has shown that the peak time of MnSOD mRNA synthesis occurs at 96 h after intermittent exercise, and this may explain why the expression of MnSOD did not change during EEP [ 49 , 67 ]. Furthermore, wortmannin had no effect on EEP in reversing various impairments, but the degree of hypoxia-ischemia showed a small increase.…”

Mitochondrial KATP Channel Function under Hypoxia

“…Thus, chronic intermittent hypoxia was shown to upregulate the system of matrix antioxidants: SOD and (CAT), which exhibited elevated expression and activity after hypoxia exposure. Higher expression of SOD, CAT and GPx found in myocardium after the exposure to intermittent hypobaric hypoxia afforded preconditioning-like effect explained by the induction of antioxidant defense [19].The effect was similar to the pretreatment of the hearts with antioxidant mixture containing SOD and CAT, which helped to restore cardiac contractile function after ischemia/reperfusion [18]. Thus, while mitochondrial ROS generated by the respiratory chain are supposed to trigger the response to hypoxia shown by the increase in [Ca 2+ ] c , HIF stabilization and triggering of redox signaling [3,4,[42][43][44], elevated expression and activation of Mn-SOD, CAT and GPx are capable to abolish or attenuate this response [48,49] and prevent excess lipid peroxidation and depletion of reduced glutathione [17].…”

“…In agreement with the present knowledge, the first step in the adaptation to hypoxia is the expression, stabilization and activation of hypoxia-inducible factor HIF, which is the transcription factor that triggers metabolic reprogramming resulting in the shift from oxidative to glycolytic metabolism [6][7][8]. Multilevel mitochondrial response to oxygen shortage includes modulations at the transcription level [6,8], morphological changes [2,9,10], alterations in the functioning of ETC at the level of respiratory complexes [11,12], shift of ATP synthesis from oxidative to glycolytic pathway [7,11,13], alterations in the mechanisms of ROS production by the respiratory chain [3,4,14], triggering of signaling pathways specific for hypoxic conditions [6,15,16] and the modulation of ROS control by matrix antioxidants [17][18][19]. These mechanisms working separately or together could explain high effectiveness of the moderate exposures to hypoxia in the adaptation of a living organism to severe oxygen deprivation, such as ischemia and anoxia [1,12].…”

Intermittent hypoxia reduces infarct size in rats with acute myocardial infarction: a systematic review and meta-analysis

“…An increasing number of studies show that IH can help reduce the area of myocardial infarction in patients with coronary heart disease [ 5 – 7 ] or in animal models of acute myocardial infarction [ 8 , 9 ]. IH can not only reduce IS but also increase the ejection fraction of the heart and reduce the occurrence of arrhythmia after AMI [ 8 , 10 , 11 ], IH also has protective effects on other organs of the body, such as lowering blood pressure, improving glucose tolerance, improving blood lipid levels, reducing the infarct area after acute cerebral infarction, and improving cognitive dysfunction and renal fibrosis after ischemia [ 1 , 2 , 12 – 15 ].…”