Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. Transforming growth factor-β1 (TGF-β1) signaling has been considered as a trigger causally contributing to pathological cardiac hypertrophy. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica and exhibits a variety of pharmacological effects. In this study, we investigated the anti-hypertrophic effects and mechanisms of action of AA in a TGF-β1-stimulated hypertrophic response using cultured neonatal cardiomyocytes in vitro and in a mouse model of cardiac hypertrophy induced by pressure overload in vivo. Treatment with AA markedly attenuated the TGF-β1-induced hypertrophic responses of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of atrial natriuretic peptide (ANP) mRNA expression. The protective effects of AA on hypertrophic cardiomyocytes were associated with the blocking of p38 and extracellular signal‑regulated kinase (ERK)1/2 phosphorylation and the reduction of nuclear factor-κB (NF-κB) binding activity. In vivo experiments indicated that the administration of AA prevented cardiac hypertrophy and dysfunction induced by pressure overload. It was found that AA markedly reduced the excessive production of TGF-β1 in the hypertrophic myocardium, blocked the phosphorylation of p38 and ERK1/2 and inhibited the activation of NF-κB. Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of TGF-β1‑mediated hypertrophic signaling may be the mechanism through which AA prevents cardiac hypertrophy.

Cardiac structural remodeling, including cardiomyocyte apoptosis, interstitial fibrosis, and inflammation, appears to be a key event associated with the progression of left ventricular hypertrophy and heart failure. Asiatic acid (AA) is a triterpenoid compound extracted from Centella asiatica that exhibits antiapoptotic, antifibrotic, and anti-inflammatory activities. In the present study, a transverse aortic constriction (TAC) model was created in mice to mimic the progression of hypertrophy (2 weeks post-TAC) and heart failure (4 weeks post-TAC) to investigate whether the potential therapeutic drug AA ameliorates hypertrophy progression and which mechanisms are involved in this amelioration. Our results demonstrated that AA markedly inhibited the process of progression induced by pressure overload. The increases cardiomyocyte apoptosis and interstitial fibrosis, and inflammatory responses were significantly suppressed by AA. Our investigation revealed that this inhibitory effect was mediated by blocking the activation of both mitochondrial and death receptor-dependent apoptotic signaling pathways. Additional experiments demonstrated that AA attenuated fibrosis by blocking both transforming growth factor-β1/Smad and interleukin-6, signaling activation. Consequently, these findings indicated that AA attenuated pathological cardiac structural remodeling and preserved cardiac function via multiple intracellular signaling pathways in response to cardiac stimuli.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease. The excessive accumulation of reactive oxygen species (ROS) during MIRI induces the overactivation of an autophagic response, which aggravates myocardial cell damage. Asiatic acid (AA) is a triterpenoid compound, which is extracted from Centella asiatica and exhibits a variety of pharmacological effects such as hepatoprotective, neuroprotective and antioxidant. However, the association of AA with autophagy in MIRI is not fully understood. In the present study, the positive effects of AA in MIRI injury were determined via establishing a MIRI mouse model. Pre-treatment with AA was indicated to improve cardiac function and decrease cardiomyocyte autophagy in mice subjected to MIRI. To examine the protective effects of AA and the underlying mechanisms in MIRI, a cardiomyocyte glucose deprivation/reperfusion (OGD) model was established. The administration of AA decreased the levels of ROS and malondialdehyde and increased the levels of superoxide dismutase activity in OGD-treated cells. Using western blotting, it was demonstrated that treatment with AA decreased the phosphorylation of p38 and increased the expression of Bcl-2 in OGD-treated cells. Additionally, the expression of autophagy markers, including beclin-1 and the microtubule-associated proteins 1A/1B light chain 3B II/I ratio, were also decreased in AA treated cells compared with OGD-treated cells. These results demonstrated that AA pretreatment protected cardiomyocytes from ROS-mediated autophagy via a p38 mitogen-activated protein kinase/Bcl-2/beclin-1 signaling pathway in MIRI.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease (CHD). Mitochondrial dysfunction is the crucial factor of MIRI; oxidative stress caused by mitochondrial reactive oxygen species (ROS) aggravates myocardial cell damage through the mitochondria-dependent apoptosis pathway. Asiatic acid (AA) is a type of pentacyclic triterpene compound purified from the traditional Chinese medicine Centella asiatica, and its protective pharmacological activities have been reported in various disease models. This study is aimed at investigating the protective effects of AA and the underlying mechanisms in MIRI. To achieve this goal, an animal model of MIRI in vivo and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) in vitro were established. The results show that AA exerts a protective effect on MIRI by improving cardiac function and reducing cardiomyocyte damage. Due to its antioxidant properties, AA alleviates mitochondrial oxidative stress, as evidenced by the stable mitochondrial structure, maintained mitochondrial membrane potential (MMP), and reduced ROS generation, otherwise due to its antiapoptotic properties. AA inhibits the mitogen-activated protein kinase (MAPK)/mitochondria-dependent apoptosis pathway, as evidenced by the limited phosphorylation of p38-MAPK and JNK-MAPK, balanced proportion of Bcl-2/Bax, reduced cytochrome c release, inhibition of caspase cascade, and reduced apoptosis. In conclusion, our study confirms that AA exerts cardiac-protective effects by regulating ROS-induced oxidative stress via the MAPK/mitochondria-dependent apoptosis pathway; the results provide new evidence that AA may represent a potential treatment for CHD patients.

Wound healing is a multistep phenomenon that relies on complex interactions between various cell types. Calpains are a well-known family of calcium-dependent cysteine proteases that regulate several processes, including cellular adhesion, proliferation, and migration, as well as inflammation and angiogenesis. CAPNS1, the common regulatory subunit of Calpain-1 and 2, is indispensable for catalytic subunit stabilization and activity. Calpain inhibition has been shown to reduce organ damage in various disease models. Here, we report that endothelial calpain-1/2 is crucially involved in skin wound healing. Using a mouse genetic model where Capns1 is deleted only in endothelial cells, we showed that calpain-1/2 disruption is associated with reduced injury-activated inflammation, reduced CD31 + blood vessel density, and delayed wound healing. Moreover, in cultured HUVECs, inhibition of calpain reduced TNF-αinduced proliferation, migration, and tube formation. Deletion of Capns1 was associated with elevated levels of IκB and downregulation of β-catenin expression in endothelial cells. These observations delineate a novel mechanistic role for calpain in the crosstalk between inflammation and angiogenesis during skin repair.

A recent genome-wide association study (GWAS) has identified a new subset of susceptibility loci of Tetralogy of Fallot (TOF), one form of cyanotic congenital heart disease (CHD), on chromosomes 10p11, 10p14, 12q24, 13q31, 15q13 and 16q12 in Europeans. In the current study, we conducted a case-control study in a Chinese population including 1,010 CHD cases [atrial septal defect (ASD), ventricular septal defect (VSD) and TOF] and 1,962 controls to evaluate the associations of these loci with risk of CHD. We found that rs2228638 in NRP1 on 10p11 was significantly increased the risk of TOF (OR = 1.52, 95% CI = 1.13–2.04, P = 0.006), but not in other subgroups including ASD and VSD. In addition, no significant associations were observed between the other loci and the risk of ASD, VSD or TOF. Our results suggested that the genetic variants on 10p11 may serve as candidate markers for TOF susceptibility in Chinese population.

Atherosclerosis (AS) is one of the leading causes of death among the elderly, and is primarily caused by foam cell generation and macrophage inflammation. Rutin is an anti-inflammatory, anti-oxidant, anti-allergic, and antiviral flavonoid molecule, known to have anti-atherosclerotic and autophagy-inducing properties, but its biological mechanism remains poorly understood. In this study, we uncovered that rutin could suppress the generation of inflammatory factors and reactive oxygen species (ROS) in ox-LDL-induced M2 macrophages and enhance their polarization. Moreover, rutin could decrease foam cell production, as shown by oil red O staining. In addition, rutin could increase the number of autophagosomes and the LC3II/I ratio, while lowering p62 expression. Furthermore, rutin could significantly inhibit the PI3K/ATK signaling pathway. In summary, rutin inhibits ox-LDL-mediated macrophage inflammation and foam cell formation by inducing autophagy and modulating PI3K/ATK signaling, showing potential in treating atherosclerosis.

To investigate the relationship of preoperative high-sensitivity cardiac troponin T (hs-cTnT) with early postoperative hypoxemia (EPH) following off-pump coronary artery bypass grafting (OPCAB). Records of patients undergoing OPCAB between 2018 and 2022 were reviewed. Baseline characteristics and postoperative arterial blood gas analysis were derived from the cardiovascular surgery electronic medical records. Preoperative hs-cTnT levels were measured routinely in all patients. Logistic regression analyses were performed to test the association of preoperative hs-cTnT with EPH. A total of 318 OPCAB patients were included, who had a preoperative hs-cTnT test available for review. Before surgery, 198 patients (62%) had a rise in hs-cTnT level (≥14 ng/L) and 127 patients (40%) had a more severe hs-cTnT level (≥25 ng/L). The preoperative hs-cTnT level was associated with EPH (odds ratio per ng/L, 1.86; 95% confidence interval 1.30–2.68; p < 0.001), prolonged intensive care unit stay (odds ratio, 1.58; 95% confidence interval 1.08–2.32; p = 0.019), and delayed extubating time (odds ratio, 1.63; 95% confidence interval 1.15–2.34; p = 0.007). On multivariable analysis, adjusted for BMI, hypertension, smoking status, serum creatinine, and cardiac function, preoperative hs-cTnT remained an independent factor associated with EPH. Elevation of hs-cTnT concentrations are significantly associated with EPH after OPCAB. Review of presurgical hs-cTnT concentration may help identify patients who would benefit from OPCAB to improve surgical risk assessment.