Mechanistic insights into the potentiation and toxicity mitigation of myocardial infarction treatment with salvianolate and ticagrelor

Abstract

Background

Ticagrelor (TG), a first-line treatment for myocardial infarction (MI), is limited in its clinical application due to the risk of elevated uric acid (UA) levels. Salvianolate injection (SAL), an adjunctive therapy for MI, has been reported to have potential for UA reduction. Although the combined use of TG and SAL has been reported in clinical practice, no studies have focused on the optimal ratio for the combination or the mechanisms underlying their synergistic effects on MI and UA reduction.

Objective

This study follows the principle of enhancing efficacy and reducing toxicity through combination therapy. It aims to explore the optimal combination ratio (low-dose combination group: 10 mg/kg TG + 10 mg/kg SAL; medium-dose combination group: 10 mg/kg TG + 20 mg/kg SAL; high-dose combination group: 20 mg/kg TG + 20 mg/kg SAL) by evaluating both UA-lowering and anti-MI activities. Additionally, the study investigates the underlying mechanisms of anti-hyperuricemia and anti-MI through metabolomics and transcriptomics, in hopes of providing insights into rational clinical use of these drugs.

Methods

Kidney H&E staining, biochemical assays (UA, BUN, XOD, CRE), in vitro XOD detection, UA transporter protein analysis (GLUT9, OAT1, ABCG2, URAT1), and bioinformatics (PI3K/AKT) were used to assess anti-hyperuricemic activity under different combination ratios. ECG, echocardiography, biochemical assays (CK, LDH), ELISA (cTnT), and H&E staining were employed to evaluate anti-MI activity. The optimal combination ratio was determined based on both anti-hyperuricemic and anti-MI effects, and metabolomics and transcriptomics were used to explore the mechanisms of anti-hyperuricemia and anti-MI for this ratio.

Results

The TG-SAL combination reduced TG-induced hyperuricemia by enhancing renal function, UA excretion, and PI3K-AKT expression, as well as inhibiting UA reabsorption and production. Simultaneously, the combination alleviated cardiac injury and restored abnormal cardiac function, demonstrating anti-MI activity. Among the groups, the medium-dose combination showed the best synergistic effect. Further, metabolomics indicated that the anti-hyperuricemic mechanism of the medium-dose combination was related to the positive regulation of selenium compound metabolic pathways. Transcriptomics revealed that the anti-MI activity of the medium-dose combination was associated with the inhibition of cardiac muscle contraction pathways.

Conclusion

The TG-SAL combination exhibited ideal synergistic effects in enhancing anti-MI activity and reducing TG-induced hyperuricemia, with the medium-dose combination demonstrating the best results. Mechanistically, the medium-dose combination exerted anti-hyperuricemic effects by positively regulating selenium compound metabolic pathways and anti-MI activity by inhibiting cardiac muscle contraction pathways. These findings provide a reference for the rational use of TG and SAL in clinical settings.