Ji Yan

Increasing glutamate promotes ischemia-reperfusion-induced ventricular arrhythmias in rats in vivo.

Background: Glutamate mediates cerebral ischemia injury via N-methyl-D-aspartate (NMDA) receptor-coupled ion channels, but the activities of glutamate in the heart remain unclear. Aims: To investigate whether or not glutamate contributes to ischemia- and reperfusion (IR)-induced arrhythmias. Methods: Myocardial IR was induced by occlusion of the left anterior descending coronary artery for 30 min and reperfusion for another 30 min. A score system was used to quantify arrhythmias. MK801 (a noncompetitive NMDA receptor antagonist), dihydrokainate (DHK, a glutamate transporter inhibitor) and gabapentin (GBP, a glutamate release inhibitor) were used before ischemia. Serum glutamate levels, Ca2+-ATPase activity, SERCA2a protein expression and myocardial mitochondrial Ca2+ content were assayed. Results: Myocardial IR caused a significant increase in serum glutamate and high incidences of ventricular arrhythmias. GBP and MK801 significantly ameliorated ventricular arrhythmias, improved SERCA2a expression and sarcoplasmic reticulum Ca2+-ATPase activity and reduced Ca2+ accumulated in mitochondria. By contrast, DHK significantly exacerbated reperfusion-related arrhythmias and mitochondrial Ca2+ overload while it decreased SERCA2a expression and activity. Conclusion: This study showed that glutamate mediates reperfusion arrhythmias, and the corresponding mechanism may be associated with Ca2+ overload via the NMDA receptor. Reperfusion arrhythmias may be prevented by inhibiting the release of glutamate or by antagonizing NMDA receptors.

Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension.

Abstract Context: Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling. The activation of RhoA/Rho-kinase (ROCK) pathway plays a central role in the pathologic progression of PH and thus the Rho kinase, an essential effector of the ROCK pathway, is considered as a potential therapeutic target to attenuate PH. Objective: In the current study, a synthetic pipeline is used to discover new potent Rho inhibitors from various natural products. Materials and methods: In the pipeline, the stepwise high-throughput virtual screening, quantitative structure–activity relationship (QSAR)-based rescoring, and kinase assay were integrated. The screening was performed against a structurally diverse, drug-like natural product library, from which six identified compounds were tested to determine their inhibitory potencies agonist Rho by using a standard kinase assay protocol. Results: With this scheme, we successfully identified two potent Rho inhibitors, namely phloretin and baicalein, with activity values of IC50 = 0.22 and 0.95 μM, respectively. Discussion and conclusion: Structural examination suggested that complicated networks of non-bonded interactions such as hydrogen bonding, hydrophobic forces, and van der Waals contacts across the complex interfaces of Rho kinase are formed with the screened compounds.

Abnormal diastolic function underlies the different beneficial effects of cardiac resynchronization therapy on ischemic and non-ischemic cardiomyopathy

OBJECTIVES: To investigate the association between diastolic function and the different beneficial effects of cardiac resynchronization therapy in patients with heart failure due to different causes. METHODS: The 104 enrolled patients were divided into an ischemic cardiomyopathy group (n=27) and a non-ischemic cardiomyopathy group (n=77) according to the cause of heart failure. Before implantation, left ventricular diastolic function was evaluated in all patients using echocardiography. After six months of follow-up, the beneficial effects of cardiac resynchronization therapy were evaluated using a combination of clinical symptoms and echocardiography parameters. RESULTS: The ischemic cardiomyopathy group included significantly more patients with restrictive filling than the non-ischemic cardiomyopathy group. The response rate after the implantation procedure was significantly higher in the non-ischemic cardiomyopathy group than in the ischemic cardiomyopathy group. Degrees of improvement in echocardiography parameters were significantly greater in the non-ischemic cardiomyopathy group than in the ischemic cardiomyopathy group. Multivariate regression analysis showed that a restrictive filling pattern was an independent factor that influenced responses to cardiac resynchronization therapy. CONCLUSIONS: This study again confirmed that the etiology of heart failure affects the beneficial effects of cardiac resynchronization therapy and a lower degree of improvement in ventricular systolic function and remodelling was observed in ischemic cardiomyopathy patients than in non-ischemic cardiomyopathy patients. In addition, systolic heart failure patients with severe diastolic dysfunction had poor responses to cardiac resynchronization therapy. Ischemic cardiomyopathy patients exhibited more severe diastolic dysfunction than non-ischemic cardiomyopathy patients, which may be a reason for the reduced beneficial effect of cardiac resynchronization therapy.