Scope Gallic acid (GA) is a dietary phenolic acid found in tea, red wine, and some plants. It exhibits anti‐oxidative and anti‐inflammatory activities. Recent studies have revealed that GA has beneficial effects against several cardiovascular diseases; however, whether GA attenuates pressure‐overload‐induced cardiac hypertrophy and the underlying mechanism remains unclear. Methods and results Primary cardiomyocyte hypertrophy is stimulated with angiotensin II (Ang II). Cardiac hypertrophic remodeling is induced in mice by transverse aortic constriction (TAC). Myocardial function is evaluated by echocardiographic and hemodynamic analyses, while cardiac tissues are analyzed by histological staining. It is observed that GA significantly decreases Ang II‐induced increases in cardiomyocyte size in vitro. Administration of GA in mice markedly improves TAC‐induced cardiac dysfunction and attenuates pathological changes, including cardiac myocyte hypertrophy, fibrosis, inflammation, and oxidative stress. Mechanistically, GA inhibits ULK1 and activates autophagy, which induces the degradation of EGFR, gp130, and calcineurin A, thereby inhibiting the downstream signaling cascades (AKT, ERK1/2, JAK2/STAT3, and NFATc1). Conclusions The results demonstrate for the first time that GA prevents myocardial hypertrophy and dysfunction via an autophagy‐dependent mechanism. Thus, GA represents a promising therapeutic candidate for treating cardiac hypertrophy and heart failure.

Background The temporal sequence between serum calcium and insulin resistance (IR) and their effects on hypertension are unclear. We studied the association between serum calcium and IR, with risk of hypertension events in a longitudinal cohort conducted in China. Methods and Results Data from 8653 subjects aged 20 to 74 years with an average follow‐up of 5.3 years were analyzed. Serum calcium, and fasting and 2‐hour serum glucose and insulin were measured at baseline and follow‐up. Cross‐lagged panel and mediation analysis were used to examine the temporal relationship between serum calcium and IR and its impact on hypertension incidence. The conjoint effects of serum calcium and IR at baseline on hypertension at follow‐up were observed ( P =0.029 for HOMA_IR [hepatic IR] and P =0.009 for Gutt index [peripheral IR]). The cross‐lagged path coefficient (β 2 ) from baseline serum calcium to follow‐up peripheral IR were significantly greater than path coefficient (β 1 ) from baseline peripheral insulin resistance to follow‐up serum calcium (β 2 =−0.354 versus β 1 =−0.005; P =0.027). However, no directional relationships were observed in the serum calcium↔hepatic IR analysis. The mediation effect of peripheral IR on the association of serum calcium at baseline with hypertension at follow‐up was estimated at 16.4% ( P <0.001). Conclusions Our findings demonstrate that higher serum calcium levels probably precede peripheral IR, and this 1‐directional relation plays a role in the development of hypertension.

Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.

Myocardial ischemia/reperfusion injury (I/RI) is closely associated with energy substrate metabolism. Fibronectin 1 (Fn1) was markedly elevated in the heart of I/R pigs and ischemic patients, but its role in myocardial I/RI is controversial and the precise mechanism involved remains elusive. Herein, we tested whether blockage of Fn1 with its inhibitor (fibronectin tetrapeptide, RGDS) would alleviate myocardial I/RI. Wild-type (WT) mice were administered with RGDS once 3 h before I/R operation and once at 24 or 48 h postreperfusion, and sacrificed at 24 or 72 h post-I/R, respectively. Cardiac function was evaluated by echocardiography. Myocardial infarction size, apoptosis, fibrosis, and inflammation were examined via histological staining. Uptake of glucose and fatty acids were detected by positron emission tomography (PET) and computer tomography (CT) with [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and [18F]-fluoro-6-thia-heptadecanoic acid (FTHA), respectively. Our results showed that administration of RGDS to mice remarkably limited the I/R-induced myocardial infarct size, myocyte apoptosis, inflammation, oxidative stress, and fibrosis and improved cardiac contractile dysfunction. These protective effects were associated with upregulation of the AMP/ATP ratio and the activation of LKB1-AMPK signaling, which subsequently increased AS160-GLUT4-mediated glucose and fatty acid uptake, improved mitochondrial dynamic imbalance, and inactivated TGF-β and NF-κB signals in the I/R heart. In conclusion, the current study identified that blocking Fn1 protects against myocardial I/RI likely through activating the LKB1-AMPK-dependent signals and highlights that inhibition of Fn1 may be a novel therapeutic option for treating ischemic heart diseases.