Chronic intermittent hypoxia accelerates cardiac dysfunction and cardiac remodeling during cardiac pressure overload in mice and can be alleviated by PHD3 overexpression

Abstract

Obstructive sleep apnea (OSA) accelerates the progression of chronic heart failure (CHF). OSA is characterized by chronic intermittent hypoxia (CIH), and CIH exposure accelerates cardiac systolic dysfunction and cardiac remodeling in a cardiac afterload stress mouse model. Mechanistic experiments showed that long-term CIH exposure activated hypoxia-inducible factor 1α (HIF-1α) expression in the mouse heart and upregulated miR-29c expression and that both HIF-1α and miR-29c simultaneously inhibited sarco-/endoplasmic reticulum calcium ATPase 2a (SERCA2a) expression in the mouse heart. Cardiac HIF-1α activation promoted cardiomyocyte hypertrophy. SERCA2a expression was suppressed in mouse heart in middle- and late-stage cardiac afterload stress, and CIH exposure further downregulated SERCA2a expression and accelerated cardiac systolic dysfunction. Prolyl hydroxylases (PHDs) are physiological inhibitors of HIF-1α, and PHD3 is most highly expressed in the heart. Overexpression of PHD3 inhibited CIH-induced HIF-1α activation in the mouse heart while decreasing miR-29c expression, stabilizing the level of SERCA2a. Although PHD3 overexpression did not reduce mortality in mice, it alleviated cardiac systolic dysfunction and cardiac remodeling induced by CIH exposure.

The Effect of HIF1-α/NF-κB/MMP2 Signaling Pathways Mediated by ALDH2 on Chronic Intermittent Hypoxia Induced Myocardial Injury in Rats

“…However, Sano et al found that HIF-1α promotes cardiac vascularization and prevents cardiac hypertrophy and contractile dysfunction from occurring [14]. Our study showed that three months of CIH resulted in high HIF-1αexpression and a decrease in LV systolic function, which is consistent with the results of a national study [5], which suggested that short-term HIF-1α upregulation provides some benefits, while long-term HIF-1α high expression over eight weeks eventually leads to myocardial damage in rats. The expression of HIF-1α is elevated under hypoxia and translocates into the nucleus to be converted into HIF-1, which binds to various target genes in the nucleus to generate a hypoxia-induced response and promote the transduction of multiple signaling pathways [5].…”

“…Our study showed that three months of CIH resulted in high HIF-1αexpression and a decrease in LV systolic function, which is consistent with the results of a national study [5], which suggested that short-term HIF-1α upregulation provides some benefits, while long-term HIF-1α high expression over eight weeks eventually leads to myocardial damage in rats. The expression of HIF-1α is elevated under hypoxia and translocates into the nucleus to be converted into HIF-1, which binds to various target genes in the nucleus to generate a hypoxia-induced response and promote the transduction of multiple signaling pathways [5]. Wei et al found that the expression levels of HIF-1α, NF-κB, IL-6, and MMP2 were significantly elevated in the state of CIH, which triggered apoptosis, myocardial fibrosis, and diminished cardiac ejection capacity [15].…”

“…Animal experiments have shown that HIF-1α transcriptional activation promotes cardiomyocyte hypertrophy [4]. Under hypoxia, the expression of HIF-1α is elevated and translocated into the nucleus to convert into HIF-1, which binds to various target genes in the nucleus to generate a hypoxia-induced response and promotes the transduction of many signaling pathways [5]. HIF, with the assistance of the hypoxia-responsive promoter, induces the transcription of the nuclear factor-kappa B (NF-κB), matrix metallopeptidase 2 (MMP2) [6,7], and regulates the expressions of reactive oxygen species (ROS) and 4-hydroxy-2-nonenal (4-HNE) [8].…”

Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

“…CIH-induced ER stress contributes to HIF-1 activation (Belaidi, Thomas et al, 2016), and reciprocally, HIF-1 activation favours ER stress (Moulin, Thomas et al, 2020). Subsequent to HIF-1/ER stress activation, CIH alters mitochondria-associated ER membranes (Moulin et al, 2022), contributing to J Physiol 601.24 alterations in calcium handling, mitochondrial function and ultimately to myocardial apoptosis and cell death (Chen et al, 2010;Xu et al, 2022;Yeung et al, 2015). In contrast to this detrimental signalling induced by sustained and persistent HIF-1 activation, short-term exposure to moderate CIH induces HIF-1-dependent cardioprotective mechanisms (i.e.…”

Epigenetics of methylation modifications in diabetic cardiomyopathy

“…Prolonged high glucose toxicity and multiple factors can induce overexpression of numerous cytokines, increased extracellular matrix production and deposition in the myocardial interstitium and perivascular areas, decreased myocardial compliance, and induced simultaneous ventricular diastolic dysfunction in late stages ( 2 , 53 , 54 ). Different promoter methylation has been reported in DCM.…”