Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin‐like modifier (SUMO)‐mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO‐specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA‐binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co‐activator yes‐associated protein 1 in the Hippo pathway. Finally, adeno‐associated virus serotype 9 is used to construct TEAD1 wild‐type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy‐related heart failure.

Mitochondrial dysfunction is a critical factor in the pathogenesis of septic cardiomyopathy (SCM). Mitochondrial anchored protein ligase (MAPL), a small ubiquitin-like modifier (SUMO) E3 ligase, plays a significant role in mitochondrial function. However, the role of MAPL in SCM remains unclear. To investigate the role of MAPL in SCM, cardiomyocyte-specific MAPL knockout mice were generated. A cecal ligation and puncture (CLP) procedure was employed to induce a sepsis-like condition. The expression of MAPL in heart tissues and H9C2 cardiomyocytes was elevated following CLP challenge or lipopolysaccharide (LPS) stimulation. MAPL deficiency ameliorated CLP-induced cardiac injury, dysfunction, and inflammation, and also improved the survival rate of mice following CLP operation. Additionally, MAPL deficiency or knockdown inhibited LPS-induced cardiomyocyte apoptosis, improved mitochondrial structural abnormalities, and increased ATP production. Furthermore, MAPL knockdown mitigated LPS-induced reductions in mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production. Mechanistically, the expression of dynamin-related protein 1 (drp1) in the mitochondria of heart tissues or H9C2 cardiomyocytes was elevated under septic conditions. Accordingly, the SUMOylation of drp1 in heart tissues or H9C2 cardiomyocytes was increased under sepsis conditions, which was reduced by MAPL knockout or knockdown. Our results reveal that MAPL promotes cardiac injury/dysfunction and inflammation in SCM. Deficiency or knockdown of MAPL alleviates SCM by reducing drp1 SUMOylation as well as drp1-mediated mitochondrial dysfunction. These findings suggest that targeting MAPL may represent a therapeutic strategy for patients with SCM.

Endothelial inflammation is crucial in the initiation and progression of atherosclerosis, while cholesterol crystals (CCs) play a key role in atherogenesis. However, the effects and origination of CCs on endothelial inflammation are not well understood. In the present study, we found that CCs appeared in the subendothelial space of the partially ligated carotid artery only one week after western diet feeding, which was before immune cell infiltration. In vitro, CCs were generated by human aortic endothelial cells (HAECs) upon LDL treatment. These EC-derived CCs increased the expression of intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1). Mechanistic studies demonstrated that CC-induced pyroptosis was critical for endothelial inflammation. Knockdown of GSDMD inhibited CC-induced endothelial inflammation, attenuated plaque progression and decreased macrophage content. Accordingly, the inhibition of GSDMD reduced the CC-induced increase of VCAM1 and ICAM1 in HAECs. Furthermore, CC-mediated pyroptosis was found to be caspase-1 (CASP1) dependent. Inhibition of CASP1 also reduced endothelial inflammation and attenuated plaque progression. In addition, the expression of GSDMD was increased in human atherosclerotic plaques. These findings identify EC-derived CCs may be an important driving force in the pathogenesis of atherosclerosis. This study uncovered a new understanding that EC-derived CC-induced pyroptosis is a key initial factor in early atherogenesis. Targeting endothelial GSDMD or CASP1 contributes to the repression of vascular inflammation and atherogenesis. Targeting endothelial GSDMD or CASP1 contributes to the repression of vascular inflammation and atherogenesis.

Septic cardiomyopathy (SC) is a sepsis-mediated cardiovascular complication characterized by cardiac dysfunction. Emerging evidence indicated that exercise training confers protection against SC; however, the underlying mechanisms are not yet fully understood. In this study, we identified a novel exercise-derived peptide, apolipoprotein A1 peptide (named ApoA1tide), through mouse plasma peptidomic screening. Subsequent experiments revealed that ApoA1tide mitigated lipopolysaccharide (LPS)-induced SC in murine models, as evidenced by enhanced cardiac function, prolonged survival, and improved myocardial structure. Moreover, ApoA1tide was found to inhibit inflammatory responses, cardiomyocyte apoptosis, and oxidative stress in mice subjected to LPS induction. Correspondingly, in vitro experiments demonstrated that ApoA1tide suppressed LPS-induced apoptosis and oxidative stress in neonatal rat cardiac myocytes (NRCMs). Additionally, ApoA1tide enhanced autophagic activity in both LPS-induced mice and NRCMs. Mechanistically, RNA sequencing identified CCAAT/enhancer-binding protein β (C/EBPβ) as the primary target of ApoA1tide. The expression of C/EBPβ was upregulated following ApoA1tide treatment. Overexpression of C/EBPβ in NRCMs resulted in increased expression of autophagy-related genes, including LC3B, Atg3, Atg4b, and Atg7. Conversely, Knockdown of C/EBPβ eliminated the enhancement of autophagy induced by ApoA1tide, along with the protective effects of ApoA1tide on cardiac functionality, cardiomyocyte apoptosis, oxidative stress, and inflammation. These findings indicate that ApoA1tide exerts its protective effects against SC by enhancing C/EBPβ-mediated autophagy. Our study provides a novel therapeutic strategy for SC. Graphical abstract Schematic representation of the effects of ApoA1tide on sepsis-induced cardiac dysfunction. ApoA1tide, a peptide derived from exercise, attenuates LPS-induced SC. This protective effect is mediated through C/EBPβ-regulated autophagy. Specifically, ApoA1tide promotes autophagy by upregulating C/EBPβ expression, which subsequently increases the expression of autophagy-related genes such as LC3B, Atg3, Atg4b, and Atg7. The enhancement of autophagy suppresses inflammatory responses, cardiomyocyte apoptosis, and oxidative stress in mice exposed to LPS, thereby ameliorating cardiac dysfunction.