Xiaoyan Yang

Ventricular arrhythmias induced by ischemia/reperfusion injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction. This study investigated the protective effects of the β2‐adrenergic receptor (β2‐AR) agonist clenbuterol against ischemia/reperfusion‐induced arrhythmias and the underlying mechanism. Anesthetized rats were subjected to 10‐min left coronary artery occlusion and 10‐min reperfusion in vivo. Langendorff‐perfused mice hearts were exposed to 10‐min global ischemia and 10‐min reperfusion. Arrhythmic events were recorded during early reperfusion. Hearts were collected for measuring nitric oxide (NO) concentration and immunoblotting of Connexin 43 (Cx43), endothelial nitric oxide synthase (eNOS), and protein kinase B (Akt). After the ischemia/reperfusion injury in anesthesia rats, clenbuterol markedly reduced the duration and incidence of ventricular tachycardia and ventricular fibrillation, and arrhythmia score, which was abrogated by selective β2‐AR antagonist or Cx43 inhibitor. Furthermore, a marked increase in dephosphorylated Cx43 expression and a decrease in the ratio of phosphorylated Cx43 to total Cx43 were observed after the ischemia/reperfusion injury. Mechanistically, clenbuterol increased the phosphorylation of e‐NOS and NO concentration, while L‐NAME abolished Cx43 phosphorylation and the protective effect of clenbuterol. Clenbuterol also promoted Akt phosphorylation, and blockade of Akt inhibited eNOS phosphorylation and NO production, as well as Cx43 phosphorylation and protective effect of clenbuterol. The present study elucidates that β2‐AR stimulation activates the Akt/eNOS signaling pathway, augments NO bioavailability, maintains Cx43 phosphorylation, and prevents Cx43 remodeling, ultimately attenuating arrhythmia induced by ischemia/reperfusion.

Psoriasis is a chronic inflammatory disease that affects approximately 1%–5% of the population worldwide. Considering frequent relapse, adverse drug reactions, and large costs of treatment, it is urgent to identify new medications for psoriasis. Keratinocytes play an essential role during psoriasis development, and they express high levels of β₂-Adrenergic receptor (β₂-AR), which increases intracellular cAMP levels when activated. Increased level of cAMP is associated with the inhibition of epidermal cell proliferation. In the present study, we observed the effect of salmeterol, a long-acting β₂-AR agonist, on the proliferation and apoptosis of keratinocytes as well as imiquimod-induced psoriasis-like skin lesions in mice. As phosphodiesterase 4 (PDE4) inhibitors increases intracellular cAMP concentration by inhibiting its inactivation, we further explored the synergetic effect of a PDE4 inhibitor and salmeterol on psoriasis-like skin lesions in mice. Our results indicated that salmeterol effectively inhibited the proliferation of HaCaT cells induced by TNF-α and serum, and this effect was accompanied by significantly increased apoptosis and CREB phosphorylation, which were reversed by the PKA inhibitor, H89. Salmeterol ameliorated imiquimod-induced psoriasis-like skin lesions in mice, but salmeterol combined with a PDE4 inhibitor had no synergetic effect in improving skin lesions in mice. Of note, the synergistic effects of anti-proliferation and induction of apoptosis in HaCaT cells appeared by inhibiting ERK signaling. In summary, salmeterol, a long-acting β₂-AR agonist, alleviates the severity of psoriasis via inhibiting the proliferation and promoting apoptosis of keratinocytes, partially by activating the cAMP/PKA signaling pathway.

To investigate the effects and the underlying mechanisms of salidroside on diabetic cardiomyopathy, diabetes was induced in mice by a long‐term high‐fat diet and a low‐dose injection of streptozocin. Measurements of cardiac function, biochemical analysis, and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. In this study, we found that diabetic mice exhibited decreased cardiac systolic function and impaired mitochondrial ultrastructure. Pre‐treatment with salidroside protected mice against myocardial dysfunction, reduced blood glucose, improved insulin resistance, and induced mitochondrial biogenesis. Neonatal rat cardiomyocytes were cultured to explore the mechanisms of salidroside in vitro. Salidroside alleviated decreased expression of peroxisome proliferator‐activated receptor‐γ coactivator 1‐alpha (PGC‐1α), mitochondrial transcription factor A (TFAM) via phosphorylation of 5′ AMP‐activated protein kinase (AMPK), which may be associated with mitochondrial biogenesis. Salidroside also increased sirtuin‐3 (SIRT3) expression in cardiomyocytes. Furthermore, salidroside promoted the translocation of SIRT3 from cytoplasm to mitochondria and increased the deacetylation of mitochondrial proteins such as manganese‐dependent superoxide dismutase (MnSOD). In Conclusion, salidroside not only improved diabetes, but also ameliorated diabetic cardiomyopathy, which was at least partly associated with the activation of mitochondrial SIRT3, AMPK/Akt, and PGC‐1α/TFAM and subsequent improving mitochondrial function.

Daurisoline (1) is a bis-benzylisoquinoline alkaloid isolated from the rhizomes of Menispermum dauricum. The antiarrhythmic effect of 1 has been demonstrated in different experimental animals. In previous studies, daurisoline (1) prolonged action potential duration (APD) in a normal use-dependent manner. However, the electrophysiological mechanisms for 1-induced prolongation of APD have not been documented. In the present study, the direct effect of 1 was investigated on the hERG current and the expression of mRNA and protein in human embryonic kidney 293 (HEK293) cells stably expressing the hERG channel. It was shown that 1 inhibits hERG current in a concentration- and voltage-dependent manner. In the presence of 10 μM 1, steady-state inactivation of V_1/2 was shifted negatively by 15.9 mV, and 1 accelerated the onset of inactivation. Blockade of hERG channels was dependent on channel opening. The expression and function of hERG were unchanged by 1 at 1 and 10 μM, while hERG expression and the hERG current were decreased significantly by 1 at 30 μM. These results indicate that 1, at concentrations below 30 μM, exerts a blocking effect on hERG, but does not affect the expression and function of the hERG channel. This may explain the relatively lower risk of long QT syndrome after long-term usage.