The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA.

Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular death worldwide. AMI with cardiomyopathy is accompanied by a poor long-term prognosis. However, limited studies have focused on the mechanism of cardiomyopathy associated with AMI. Pericytes are important to the microvascular function in the heart, yet little attention has been paid to their function in myocardial infarction until now. In this study, we integrated single-cell data from individuals with cardiomyopathy and myocardial infarction (MI) GWAS data to reveal the potential function of pericytes in cardiomyopathy-associated MI. We found that pericytes were concentrated in the left atrium and left ventricle tissues. DLC1/GUCY1A2/EGFLAM were the top three uniquely expressed genes in pericytes (p < 0.05). The marker genes of pericytes were enriched in renin secretion, vascular smooth muscle contraction, gap junction, purine metabolism, and diabetic cardiomyopathy pathways (p < 0.05). Among these pathways, the renin secretion and purine metabolism pathways were also found in the process of MI. In cardiomyopathy patients, the biosynthesis of collagen, modulating enzymes, and collagen formation were uniquely negatively regulated in pericytes compared to other cell types (p < 0.05). COL4A2/COL4A1/SMAD3 were the hub genes in pericyte function involved in cardiomyopathy and AMI. In conclusion, this study provides new evidence about the importance of pericytes in the pathogenesis of cardiomyopathy-associated MI. DLC1/GUCY1A2/EGFLAM were highly expressed in pericytes. The hub genes COL4A2/COL4A1/SMAD3 may be potential research targets for cardiomyopathy-associated MI.

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.

Background: Cardiovascular complications stemming from diabetes pose a grave threat to patients’ survival. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) significantly increase the risk of heart failure, yet no reports have clarified whether there are differences in the pathway alterations involved in these two conditions. Investigating the heterogeneity of the cardiac remodeling between these two types of diabetes is conducive to reducing the incidence of cardiovascular events in diabetic patients in clinical practice. Methods: T1D and T2D models were established in adult mice, and the hearts were collected for RNA sequencing. Differential expression analysis (DEA) was performed. Integrating functional enrichment analyses, we probed into gene and pathway heterogeneity. Subsequently, we compared single-cell RNA sequencing (scRNA-seq) data of hearts from T1D and T2D mice, focusing on three cell populations (endothelial cells, macrophages, and fibroblasts) to identify gene and pathway differences. Finally, we evaluated shared genes and common signaling pathway changes across these three cell populations in both diabetes types. Results: We have successfully established T1D and T2D models in mice. Compared with shared genes, the two types of diabetes had more consistent pathway changes. Further scRNA-seq analysis identified endothelial cells, macrophages, and fibroblasts as significantly associated with the diabetic phenotype. In shared pathway, endothelial cells were significantly enriched in pathways related to endothelial proliferation and angiogenesis; macrophages were enriched in immune response pathways; and fibroblasts were enriched in pathways involving fibrosis, cell proliferation, and apoptosis. In endothelial cells, inflammatory response and fatty acid metabolism pathways were predominantly enriched in T1D, while energy metabolism pathways were dominant in T2D. In macrophages, antiviral immune pathways were specifically enriched in T1D, whereas macrophages in T2D were additionally implicated in the regulation of cardiomyocyte function. In fibroblasts, immune-related pathways were characteristically enriched in T1D, while cell respiration and energy supply pathways were prominent in T2D. Common functional enrichment pathways across the three cell types in both diabetes types mainly involved innate immune responses and cardiac morphogenesis, with the proportion of shared pathways being significantly higher than that of shared genes. Conclusions: This study, by combining RNA sequencing and scRNA-seq, revealed that cardiac pathologies induced by T1D and T2D exhibit a higher degree of consistent pathway changes compared to shared gene changes. Interventions targeting these common pathways may hold greater value in preventing and treating diabetic cardiomyopathy.