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

Abstract

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.

Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure

“…It has been reported that the BMP pathway is enriched for HFpEF but not HFrEF ( 26 ). BMP2 has been found to alleviate heart failure with type 2 diabetes by inhibiting inflammasome formation ( 27 ), and is inversely correlated with the concentrations of atrial natriuretic peptide and brain natriuretic peptide in chronic heart failure patients with diabetes. Another study observed increased BMP6 in chronic heart failure patients, suggesting that BMP6 may be involved in the pathophysiology of systolic heart failure ( 28 ).…”

The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy

“…Meanwhile, the tight correlation between chemotherapy-induced tissue damage and pyroptosis also provides a promising strategy to reduce toxicity by inhibition of pyroptosis. For instance, DOX, a common antineoplastic agent, can cause cardiotoxicity via pyroptosis in clinical practice [ 193 – 195 ]. MCC950, an NLRP3 inflammasome inhibitor, could obviously suppress myocardial inflammation and fibrosis by inhibiting pyroptosis of cardiomyocyte in DOX-treated mice [ 193 ].…”

Echinacoside inhibited cardiomyocyte pyroptosis and improved heart function of HF rats induced by isoproterenol via suppressing NADPH/ROS/ER stress

“…NOD‐like receptor protein 3 (NLRP3) inflammasome is a key factor of pyroptosis, and after activation, NLRP3 interacts with apoptosis‐associated speck‐like protein (ASC), recruits and cleaves pro‐caspase‐1, thus activating caspase‐1, which cleaves gasdermin D(GSDMD) with producing GSDMD‐N, and further triggers the pyroptotic cascade (activated caspase‐1 induces inflammation by cleaving pre‐interleukin [IL]‐1β and pre‐IL‐18 into IL‐1β and IL‐18, which are biomarkers of pyroptotic) 5 . In recent years, studies confirmed that NLRP3 inflammasome is activated during several cardiac disorders, and NLRP3 inflammasome‐mediated pyroptosis aggravates pressure overload‐induced cardiac hypertrophy, fibrosis, dysfunction, 6 which is a key pathological factor underlying HF 7–9 …”

“…5 In recent years, studies confirmed that NLRP3 inflammasome is activated during several cardiac disorders, and NLRP3 inflammasome-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, dysfunction, 6 which is a key pathological factor underlying HF. [7][8][9] ROS acts as a major trigger of NLRP3 inflammasome activation, 10 NADPH oxidase, mainly subunit NOX2 and NOX4, is the main source of intracellular ROS, and the expression of NADPH is up-regulated in HF. 11,12 ER is essential for protein synthesis, protein folding, protein translocation and calcium homoeostasis.…”