PLIN5 Suppresses Lipotoxicity and Ferroptosis in Cardiomyocyte via Modulating PIR/NF-κB Axis.

Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL)-1ß/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.

BMP-2 alleviates heart failure with type 2 diabetes mellitus and doxorubicin-induced AC16 cell injury by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Chronic heart failure (CHF) and diabetes mellitus are associated with morbidity and mortality. CHF and diabetes generally simultaneously occur, resulting in adverse outcomes. Diabetes complicates cardiomyopathy and exacerbates heart failure conditions. An increase in natriuretic peptides, including atrial natriuretic peptide (ANP), and another endsogenously generated peptide, brain natriuretic peptide (BNP), serves an essential role in CHF. The aim of this study was to explore the molecular regulation between bone morphogenetic protein-2 (BMP-2) and ANP or BNP in diabetes-associated cardiomyopathy. In total, 25 serum samples were collected from patients with CHF with or without type 2 diabetes mellitus to compare with 25 controls. Cardiomyopathy and hyperglycemia were induced in rats by doxorubicin and streptozotocin, respectively. AC16 cells were used to study molecular mechanisms. BMP, ANP and BNP concentration in patients and rats were measured by ELISA. Flow cytometry was performed to analyze cell pyroptosis and ROS production. Reverse transcription-quantitative PCR and western blotting were used to examine mRNA and protein expression of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), pro-caspase-1, caspase-1 (p20) and gasdermin D. BMP-2 was negatively correlated with ANP and BNP in CHF patients with type 2 diabetes mellitus. Similar results were obtained in rats and AC16 cells. BMP-2 decreased the NLRP3 inflammasome activation and cell pyroptosis. The present study found evidence that the cardioprotective effects of BMP-2 act through ANP and BNP both in vivo and in vitro. BMP-2 inhibits inflammasome formation. The results suggested that BMP-2 may serve as a novel therapeutic target for the treatment of diabetic heart conditions.