BRD7 mediates hyperglycaemia‐induced myocardial apoptosis via endoplasmic reticulum stress signalling pathway

Diabetic cardiomyopathy, a major cardiac complication, contributes to heart remodelling and heart failure. Our previous study discovered that CCAAT/enhancer‐binding protein β (C/EBPβ), a transcription factor that belongs to a family of basic leucine zipper transcription factors, interacts with the angiotensin‐converting enzyme 2 (ACE2) promoter sequence in other disease models. Here, we aimed to determine the role of C/EBPβ in diabetes and whether ACE2 expression is regulated by C/EBPβ. A type 1 diabetic mouse model was generated by an intraperitoneal injection of streptozotocin. Diabetic mice were injected with a lentivirus expressing either C/EBPβ or sh‐C/EBPβ or treated with valsartan after 12 weeks to observe the effects of C/EBPβ. In vitro, cardiac fibroblasts and cardiomyocytes were treated with high glucose (HG) to investigate the anti‐fibrosis, anti‐apoptosis and regulatory mechanisms of C/EBPβ. C/EBPβ expression was down‐regulated in diabetic mice and HG‐induced cardiac neonatal cells. C/EBPβ overexpression significantly attenuated collagen deposition and cardiomyocyte apoptosis by up‐regulating ACE2 expression. The molecular mechanism involved the binding of C/EBPβ to the ACE2 promoter sequence. Although valsartan, a classic angiotensin receptor blocker, relieved diabetic complications, the up‐regulation of ACE2 expression by C/EBPβ overexpression may exert greater beneficial effects on patients with diabetic cardiomyopathy.

Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

CCAAT/enhancer‐binding protein β overexpression alleviates myocardial remodelling by regulating angiotensin‐converting enzyme‐2 expression in diabetes

Tie

Zhai

Zhang

et al. 2017

“…Mice were anesthetized with 1.5% isoflurane, and echocardiographic images were evaluated using the VEVO770 imaging system (VisualSonics) as described previously . Adequate depth of anaesthesia was monitored using toe reflex.…”

Section: Methodsmentioning

confidence: 99%

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

Zuo

Zhao

et al. 2020

CTRP9 has been reported to regulate lipid metabolism and exert cardioprotective effects, yet its role in high‐fat diet (HFD)‐induced cardiac lipotoxicity and the underlying mechanisms remain unclear. In the current study, we established HFD‐induced obesity model in wild‐type (WT) or CTRP9 knockout (CTRP9‐KO) mice and palmitate‐induced lipotoxicity model in neonatal rat cardiac myocytes (NRCMs) to investigate the effects of CTRP9 on cardiac lipotoxicity. Our results demonstrated that the HFD‐fed CTRP9‐KO mice accentuated cardiac hypertrophy, fibrosis, endoplasmic reticulum (ER) stress‐initiated apoptosis and oxidative stress compared with the HFD‐fed WT mice. In vitro, CTRP9 treatment markedly alleviated palmitate‐induced oxidative stress and ER stress‐induced apoptosis in NRCMs in a dose‐dependent manner. Phosphorylated AMPK at Thr172 was reduced, and phosphorylated mammalian target of rapamycin (mTOR) was strengthened in the heart of the HFD‐fed CTRP9‐KO mice compared with the HFD‐fed control mice. In vitro, AMPK inhibitor compound C significantly abolished the effects of CTRP9 on the inhibition of the apoptotic pathway in palmitate‐treated NRCMs. In a further mechanistic study, CTRP9 enhanced expression of phosphorylated LKB1 at Ser428 and promoted LKB1 cytoplasmic localization. Besides, silencing of LKB1 gene by lentivirus significantly prohibited activation of AMPK by CTRP9 and partially eliminated the protective effect of CTRP9 on the cardiac lipotoxicity. These results indicate that CTRP9 exerted anti‐myocardial lipotoxicity properties and inhibited cardiac hypertrophy probably through the LKB1/AMPK signalling pathway.

“…TUNEL assay was used at the cell apoptosis assay. 19 For DNA fragmentation, TUNEL assays kit (Millipore, USA) was used to treat the H9c2 cardiomyoblasts or tissue sections according to manufacturer's instructions. Briefly, cells were fixed with 4% paraformaldehyde for 10 min at room temperature and then washed with PBS twice.…”

Section: Tunel Stainingmentioning

confidence: 99%

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway

Wang

Pan

Liu

et al. 2019

Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti‐apoptotic role in diabetic cardiomyopathy. Sprague‐Dawley rats were fed with high‐fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl‐2, bax and caspase‐3 were measured. 5‐HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 µmol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5‐HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.