Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders

Packer, Milton

doi:10.1016/j.jacbts.2020.05.006

Cited by 60 publications

(63 citation statements)

References 104 publications

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“…These authors also proposed several SGLT2-associated renal mechanisms that included increased β-hydroxybutyrate levels and expression of hypoxia-inducible factors (HIFs) [ 34 ]. Furthermore, the increase in erythropoiesis may be explained by SGLT2 inhibitor-mediated activation of sirtuin-1 signaling and subsequent regulation of imbalances in HIF-1α and HIF-2α [ 35 ]. Taken together these findings indicate that increased erythropoiesis associated with SGLT2 inhibition appears to reflect favorable intra-renal responses, rather than simple hemoconcentration through loss of intravascular fluid volume.…”

Section: Discussionmentioning

confidence: 99%

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

Tanaka

Shimabukuro

Teragawa

et al. 2021

Cardiovasc Diabetol

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Backgrounds/Aim Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). Methods The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. Results In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by − 2.23% (95% CI − 5.72 to 1.25) at week 4, − 8.07% (− 12.76 to − 3.37) at week 12, and − 5.60% (− 9.87 to − 1.32) at week 24; eEV by − 70.3 mL (95% CI − 136.8 to − 3.8) at week 4, − 135.9 mL (− 209.6 to − 62.3) at week 12, and − 144.4 mL (− 226.3 to − 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. Conclusions Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502

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Section: Discussionmentioning

confidence: 99%

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

Tanaka

Shimabukuro

Teragawa

et al. 2021

Cardiovasc Diabetol

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“…Roxadustat, a new drug designed for renal anemia ( Chen et al, 2019b ), has been shown to inhibit hypoxia-inducible factor (HIF) and alleviate the progression of renal fibrosis ( Packer, 2020 ). Li et al (2020b) have implemented animal research to figure out that Roxadustat may retard the progression of fibrosis by regulating Akt/GSK-3β-dependent Nrf2 activation.…”

Section: New Therapies For Renal Fibrosismentioning

confidence: 99%

Signaling Pathways Involved in Diabetic Renal Fibrosis

Zhang

Jin

Kang

et al. 2021

Front. Cell Dev. Biol.

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Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

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“…After years of investigation into the molecular pathophysiology of cardiac fibrosis in patients and experimental animals, it has been found that the mice subjected to TAC‐induced pressure overload manifest rapid cardiac decompensation with excess cardiac fibrosis and increased myocardial hypoxia 16 . HIF‐1α, which is essential for maintaining O 2 homeostasis, is activated in response to increased oxygen demand and relative hypoxia during pressure overload‐induced myocardial hypertrophy and fibrosis 21 . Therefore, the TAC model, which includes chronic ischemia and/or hypoxia has been identified as one of the most suitable models for hypoxia‐induced myocardial fibrosis 9,17 .…”

Section: Discussionmentioning

confidence: 99%

Low‐intensity pulsed ultrasound prevents prolonged hypoxia‐induced cardiac fibrosis through HIF‐1α/DNMT3a pathway via a TRAAK‐dependent manner

Zhao

Weng

et al. 2021

Clin Exp Pharma Physio

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Hypoxia‐induced cardiac fibrosis is an important pathological process in cardiovascular disorders. This study aimed to determine whether low‐intensity pulsed ultrasound (LIPUS), a novel and safe apparatus, could alleviate hypoxia‐induced cardiac fibrosis, and to elucidate the underlying mechanisms. Hypoxia (1% O2) and transverse aortic constriction (TAC) were performed on neonatal rat cardiac fibroblasts and mice to induce cardiac fibrosis, respectively. LIPUS irradiation was applied for 20 minutes every 6 hours for a total of 2 times in vitro, and every 2 days from 1 week before surgery to 4 weeks after surgery in vivo. We found that LIPUS dose‐dependently attenuated hypoxia‐induced cardiac fibroblast phenotypic conversion in vitro, and ameliorated TAC‐induced cardiac fibrosis in vivo. Hypoxia significantly upregulated the nuclear protein expression of hypoxia‐inducible factor‐1α (HIF‐1α) and DNA methyltransferase 3a (DNMT3a). LIPUS pre‐treatment reversed the elevated expression of HIF‐1α, and DNMT3a. Further experiments revealed that HIF‐1α stabilizer dimethyloxalylglycine (DMOG) hindered the anti‐fibrotic effect of LIPUS, and hampered LIPUS‐mediated downregulation of DNMT3a. DNMT3a small interfering RNA (siRNA) prevented hypoxia‐induced cardiac fibrosis. Results also showed that the mechanosensitive protein‐TWIK‐related arachidonic acid‐activated K+ channel (TRAAK) messenger RNA (mRNA) expression was downregulated in hypoxia‐induced cardiac fibroblasts, and TAC‐induced hearts. TRAAK siRNA impeded LIPUS‐mediated anti‐fibrotic effect and downregulation of HIF‐1α and DNMT3a. Above results indicated that LIPUS could prevent prolonged hypoxia‐induced cardiac fibrosis through TRAAK‐mediated HIF‐1α/DNMT3a signalling pathway.

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Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders

Cited by 60 publications

References 104 publications

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

Signaling Pathways Involved in Diabetic Renal Fibrosis

Low‐intensity pulsed ultrasound prevents prolonged hypoxia‐induced cardiac fibrosis through HIF‐1α/DNMT3a pathway via a TRAAK‐dependent manner

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