Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

Abstract

WHAT THIS PAPER ADDS Thoracic aortic dissection (TAD) is a life threatening cardiovascular disorder. Intermittent hypoxia (IH) triggers beneficial effects in multiple physiological systems, such as hypertension and coronary heart disease, in clinical and animal models. It was found that IH alleviates b-aminopropionitrile monofumarate induced TAD in C57BL/6 mice. Future studies should focus on the specific mechanism of thez protective role of IH and whether IH might be a treatment method for TAD. Objective: Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. Methods: b-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n ¼ 30) (21%e5% O 2 , 90 s/cycle, 10 h/day, IH þ BAPN group) or normoxia (n ¼ 30) (21% O 2 , 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O 2)/re-oxygenation (30 min, 21% O 2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1a and LOX via HIF-1a-siRNA. Results: It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1b, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1a. Conclusion: The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.

Moderate aerobic exercise prevents matrix degradation and death in a mouse model of aortic dissection and aneurysm

“…The consequences of LOX inhibition with BAPN treatment were evidenced by significant elastin fragmentation, aortic wall remodeling, and identification of abnormal cell-matrix interactions, which recapitulate human disease. The mortality rate, aneurysm incidence, and histologic changes associated with BAPN treatment reported by our group are consistent with what others have published using this model (31,33,(43)(44)(45)(46). We demonstrate that moderate aerobic exercise dramatically reduces the incidence of thoracic aortic dissection and aneurysm, pathologic aortic wall remodeling, and associated aortic rupture and mortality.…”

lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195

“…The cat K/caspase-8 axis is a key initial step for oxidative stress (47), and cat K ablation is known to mitigate high-fat-diet-induced cardiomyocyte apoptosis and cardiac hypertrophy (48). However, the role of the FGd5-aS1/mir-195/rora axis in cat S/K expression levels was not determined in the present study, although previous studies have demonstrated that cat S and cat K are downregulated in intermittent hypoxia-treated and ischemia-induced mice, respectively (49,50). Moreover, cat K has been revealed to promote proliferation, migration and tube formation of human vascular endothelial cells under hypoxia via acting as target of mir-185-5p and the notch 1 signaling pathway (50,51).…”

Chronic Transient Hypoxia Alleviates High Fat Diet-Induced Obesity and Fatty Liver in C57 Mice by Upregulating Epinephrine Levels and Activation of AMPK

“…Yet the study of oxygen concentration is still needed to be clari ed, which are primarily due to the different methods of hypoxia (time, oxygen concentration, hypoxia mode, etc.) [7], and the conclusions drawn are not consistent.…”

“…It is well established that exercise stimulates the production of epinephrine [8], and hypoxia environment as a stimulus also increases the level of epinephrine [9]. However, the current research methods on hypoxia due to the prolonged exposure to hypoxia, the oxygen concentration is too low, and the pattern of hypoxia is complicated [7], which become limiting factors for the signi cance of clinical application. We expect that our chronic transient hypoxia environment can achieve the effect of exercise, our research found that when mice are exposed to 10% oxygen for one hour every day, it can slow down the weight gain of high-fat-induced obese mice (DIO) and remission the severity of fatty liver, it also activation of AMPK, induction of M2 type macrophage marker CD206 expression in liver and elevated levels of serum epinephrine.…”