Eccentric cardiac hypertrophy was induced by long‐term intermittent hypoxia in rats

Abstract

It is unclear whether cardiac hypertrophy and hypertrophy-related pathways will be induced by long-term intermittent hypoxia. Thirty-six Sprague-Dawley rats were randomly assigned into three groups: normoxia, and long-term intermittent hypoxia (12% O 2 , 8 h per day) for 4 weeks (4WLTIH) or for 8 weeks (8WLTIH). Myocardial morphology, trophic factors and signalling pathways in the three groups were determined by heart weight index, histological analysis, Western blotting and reverse transcriptase-polymerase chain reaction from the excised left ventricle. The ratio of whole heart weight to body weight, the ratio of left ventricular weight to body weight, the gross vertical cross-section of the heart and myocardial morphological changes were increased in the 4WLTIH group and were further augmented in the 8WLTIH group. In the 4WLTIH group, tumour necrosis factor-α(TNFα), insulin-like growth factor (IGF)-II, phosphorylated p38 mitogen-activated protein kinase (P38), signal transducers and activators of transcription (STAT)-1 and STAT-3 were significantly increased in the cardiac tissues. However, in the 8WLTIH group, in addition to the above factors, interleukin-6, mitogen-activated protein kinase (MEK)5 and extracellular signal-regulated kinase (ERK)5 were significantly increased compared with the normoxia group. We conclude that cardiac hypertrophy associated with TNFα and IGF-II was induced by intermittent hypoxia. The longer duration of intermittent hypoxia further activated the eccentric hypertrophy-related pathway, as well as the interleukin 6-related MEK5-ERK5 and STAT-3 pathways, which could result in the development of cardiac dilatation and pathology.

Long-term hypoxia exposure enhanced IGFBP-3 protein synthesis and secretion resulting in cell apoptosis in H9c2 myocardial cells

“…LTIHH promoted cardiac hypertrophy (Chen et al, 2007;Hsieh et al, 2014), fibrosis and cardiac apoptotic activities (Lee et al, 2007;Lin et al, 2008). These findings suggest that hypoxia challenge exerts deleterious effects on the heart.…”

“…Evidence from several studies indicated that hypoxia can trigger apoptosis in cardiomyocytes (Sellinger et al, 2015;Yan et al, 2014). Our previous studies showed that long-term intermittent hypoxia could result in eccentric cardiac hypertrophy in rats (Chen et al, 2007) and induce both mitochondrial-dependent apoptotic and Fas death receptor-dependent apoptotic pathways in rat hearts (Lee et al, 2007). Results from several studies suggested that cardiomyocyte apoptosis is a critical factor in the initiation and progression of many types of cardiac disease (Konstantinidis et al, 2012) such as ischemia/reperfused heart MI and end-stage heart failure (Jiang et al, 2014;Lim et al, 2014;Xu et al, 2014).…”

Mitogen-Activated Protein Kinases in Heart Development and Diseases

“…139 Activation ERK5 also was associated with eccentric hypertrophy in-duced by intermittent hypoxia in rat. 140 Therefore, a specific role of ERK5 in eccentric hypertrophy as opposed to other forms of cardiac remodeling was proposed. However, a recent study showed that an activated cardiac isoform, MEK5␣, failed to induce hypertrophy in transgenic mice but rather conferred strong cardiac protection against ischemia/ reperfusion injury.…”

Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats

“…The ERK5 pathway was also induced by gp130 and played a crucial role in eccentric hypertrophy (Nakaoka et al 2010). MEK5-ERK5 signaling was triggered by IL-6 induced serial assembly of sarcomeres and eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death (Nicol et al 2001;Chen et al 2007). The activation or phosphorylation of p38 or JNK MAPK was found to mediate cardiac remodeling and hypertrophy, and heart failure in pressure overload model (Bartha et al 2009), evidenced in the increase of myocyte hypertrophy and expression of natriuretic peptides ANP and BNP in vitro and in vivo (Koivisto et al 2011;Ye et al 2010).…”