Rapid over-activation of β-adrenergic receptor (β-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute β-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon β-AR insult. Male C57BL/6 mice were injected with a single dose of β-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon β-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1β, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced β₁-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. Inflammasome-dependent activation of IL-18 within the myocardium upon acute β-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of β-AR insult can successfully prevent inflammatory responses and cardiac injuries.

Background—: The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2). Methods and Results—: Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell–specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas. Conclusions—: Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.

Membrane nanotubes (MNTs) act as “highways” between cells to facilitate the transfer of multiple signals and play an important role in many diseases. Our previous work reported on the transfer of mitochondria via MNTs between cardiomyocytes (CMs) and cardiac myofibroblasts (MFs); however, the elucidation of the underlying mechanism and pathophysiological significance of this transfer requires additional study. In this study, we determined that the mean movement velocity of mitochondria in MNTs between CMs and MFs was approximately 17.5 ± 2.1 nm/s. Meanwhile, treatment with microtubule polymerisation inhibitors nocodazole or colcemid in cell culture decreased mitochondrial velocity, and knockdown of the microtubule motor protein kinesin family member 5B (KIF5B) led to a similar effect, indicating that mitochondrial movement was dependent on microtubules and the motor protein KIF5B. Furthermore, we showed that hypoxia/reoxygenation-induced CM apoptosis was attenuated by coculture with intact or hypoxia/reoxygenation-treated MFs, which transferred mitochondria to CMs. This rescue was prevented either by separating the cells using Transwell culture or by impairing mitochondrial transfer with nocodazole or colcemid treatment. In conclusion, as a novel means of intercellular communication, MNTs rescue distressed CMs from apoptosis by transporting mitochondria along microtubules via KIF5B.

Metformin is a widely used first-line antidiabetic drug that has been shown to protect against a variety of specific diseases in addition to diabetes, including cardiovascular disorders, polycystic ovary syndrome and cancer. However, the precise mechanisms underlying the diverse therapeutic effects of metformin remain elusive. Here, we report that transforming growth factor-β1 (TGF-β1), which is involved in the pathogenesis of numerous diseases, is a novel target of metformin. Using a surface plasmon resonance-based assay, we identified the direct binding of metformin to TGF-β1 and found that metformin inhibits [¹²⁵I]-TGF-β1 binding to its receptor. Furthermore, based on molecular docking and molecular dynamics simulations, metformin was predicted to interact with TGF-β1 at its receptor-binding domain. Single-molecule force spectroscopy revealed that metformin reduces the binding probability but not the binding force of TGF-β1 to its type II receptor. Consequently, metformin suppresses type II TGF-β1 receptor dimerization upon exposure to TGF-β1, which is essential for downstream signal transduction. Thus, our results indicate that metformin is a novel TGF-β suppressor with therapeutic potential for numerous diseases in which TGF-β1 hyperfunction is indicated.

Inflammation promotes the development of heart failure (HF). The inflammasome is a multimeric protein complex that plays an essential role in the innate immune response by triggering the cleavage and activation of the proinflammatory cytokines interleukins (IL)-1β and IL-18. Blocking IL-1β with the monoclonal antibody canakinumab reduced hospitalizations and mortality in HF patients, suggesting that the inflammasome is involved in HF pathogenesis. The inflammasome is activated under various pathologic conditions that contribute to the progression of HF, including pressure overload, acute or chronic overactivation of the sympathetic system, myocardial infarction, and diabetic cardiomyopathy. Inflammasome activation is responsible for cardiac hypertrophy, fibrosis, and pyroptosis. Besides inflammatory cells, the inflammasome in other cardiac cells initiates local inflammation through intercellular communication. Some inflammasome inhibitors are currently being investigated in clinical trials in patients with HF. The current evidence suggests that the inflammasome is a critical mediator of cardiac inflammation during HF and a promising therapeutic target. The present review summarizes the recent advances in both basic and clinical research on the role of the inflammasome in HF.