Shexiang Tongxin dropping pill ameliorates microvascular obstruction via downregulating ALOX12 after myocardial ischemia-reperfusion.

BACKGROUND: Microvascular dysfunction (MVD) is common in patients with myocardial infarction receiving reperfusion therapy and is associated with adverse cardiac prognosis. Accumulating evidence suggests a protective role of Shexiang Tongxin dropping pill (STDP) in MVD. However, the specific effects and the underlying mechanisms of STDP in the context of MVD after myocardial ischemia-reperfusion (IR) remains unclear. AIMS: We aimed to elucidate the role of STDP in MVD induced by IR and the potential mechanisms involved. METHODS: Mice were orally administered with STDP or normal saline for 5 days before receiving myocardial IR. Cardiac function and microvascular obstruction was measured. Proteomics and single-cell RNA sequencing was performed on mouse hearts. In vitro hyoxia/reoxygenation model was established on mouse cardiac microvascular endothelial cells (MCMECs). RESULTS: STDP improved cardiac function and decreased microvascular obstruction (MVO) in mice after myocardial IR. Proteomics identified ALOX12 as an important target of STDP. Single-cell RNA sequencing further revealed that downregulation of ALOX12 by STDP mainly occurred in endothelial cells. The involvement of ALOX12 in the effect of STDP on MVO was validated by manipulating ALOX12 via endothelial-specific adeno-associated virus transfection in vivo and in vitro. In vivo, overexpression of ALOX12 increased whereas knockdown of ALOX12 decreased MVO and thrombus formation. STDP treatment alleviated the detrimental effects of overexpression of ALOX12. In vitro, overexpression of ALOX12 increased endothelial cell inflammation and platelet adhesion to endothelial cells, which was abolished by STDP treatment. CONCLUSION: Our findings suggest that STDP alleviates MVO after IR, with ALOX12 playing a crucial role.

Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension.

INTRODUCTION: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. METHODS: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). RESULTS: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. CONCLUSIONS: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.