Activating transcription factor 4 drives the progression of diabetic cardiac fibrosis

Abstract

Aims Diabetic cardiomyopathy (DC) is one of serious complications of diabetic patients. This study investigated the biological function of activating transcription factor 4 (ATF4) in DC. Methods and results Streptozotocin‐treated mice and high glucose (HG)‐exposed HL‐1 cells were used as the in vivo and in vitro models of DC. Myocardial infarction (MI) was induced by left coronary artery ligation in mice. Cardiac functional parameters were detected by echocardiography. Target molecule expression was determined by real time quantitative PCR and western blotting. Cardiac fibrosis was observed by haematoxylin and eosin and Masson's staining. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling. Activities of superoxide dismutase, glutathione peroxidase, and levels of malonic dialdehyde and reactive oxygen species were used to assess oxidative stress damage. Molecular mechanisms were evaluated by chromatin immunoprecipitation, dual luciferase assay, and co‐immunoprecipitation. ATF4 was up‐regulated in the DC and MI mice (P < 0.01). Down‐regulation of ATF4 improved cardiac function as evidenced by changes in cardiac functional parameters (P < 0.01), inhibited myocardial collagen I (P < 0.001) and collagen III (P < 0.001) expression, apoptosis (P < 0.001), and oxidative stress (P < 0.001) in diabetic mice. Collagen I (P < 0.01) and collagen III (P < 0.01) expression was increased in MI mice, which was reversed by ATF4 silencing (P < 0.05). ATF4 depletion enhanced viability (P < 0.01), repressed apoptosis (P < 0.001), oxidative damage (P < 0.001), and collagen I (P < 0.001), and collagen III (P < 0.001) expression of HG‐stimulated HL‐1 cells. ATF4 transcriptionally activated Smad ubiquitin regulatory factor 2 (Smurf2, P < 0.001) to promote ubiquitination and degradation of homeodomain interacting protein kinase‐2 (P < 0.001) and subsequently caused inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway (P < 0.001). The inhibitory effects of ATF4 silencing on HG‐induced apoptosis (P < 0.01), oxidative injury (P < 0.01), collagen I (P < 0.001), and collagen III (P < 0.001) expression were reversed by Smurf2 overexpression. Conclusions ATF4 facilitates diabetic cardiac fibrosis and oxidative stress by promoting Smurf2‐mediated ubiquitination and degradation of homeodomain interacting protein kinase‐2 and then inactivation of nuclear factor erythroid 2‐related factor 2/heme oxygenase 1 pathway, suggesting ATF4 as a treatment target for DC.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy

“…In addition to Tcf21, Arnt, Stat5a, and Stat5b, previous studies have explored and demonstrated the significant roles of other transcription factors in DCM. For instance, ATF4 [59] in DCM promotes cardiac fibrosis and oxidative stress, while downregulation of Bmal1 [60] induces mitochondrial dysfunction by promoting Bcl2/IP3Rmediated mitochondrial Ca 2+ overload, leading to diabetic cardiomyopathy. A recent study has also revealed that ketone bodies can rescue mitochondrial dysfunction through epigenetic remodeling [61].…”

Editors' highlight picks from 2023 in ESC heart failure

“…60 In a preclinical study conducted in in vivo and in vitro rodent models, transcription factor 4 (ATF4) was identified as a regulator of apoptosis and fibrosis. 61 Heart failure associated metabolic derangements develop not only in adults but also in children, 62 and these alterations are further aggravated by diabetic cardiomyopathy where metabolic alterations via dyslipidaemia and subsequent lipid-induced toxicity (i.e. lipotoxicity) harm and limit the function of the cardiovascular system.…”