Huangqi Guizhi Wuwu Decoction alleviates diabetic cardiovascular autonomic neuropathy via AMPK/TrkA/TRPM7 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE

Diabetic cardiac autonomic neuropathy (DCAN) is one of the serious complications of diabetes and greatly increased the risk of cardiovascular disease mortality. Huangqi Guizhi Wuwu Decoction (HGWD) has been proven effective for DCAN, while the underlying mechanism remains unclarified.

AIM OF THE STUDY

To observe the clinical efficacy of HGWD on DCAN and elucidate its potential mechanisms with the animal model.

MATERIALS AND METHODS

In this study, a total of 202 patients who met the inclusion criteria were recruited for the clinical trial and were randomly divided into two groups. Betaloc® Zok was used as the positive drug. The effect of HGWD on heart rate variability in DCAN patients was observed. To further clarify its underlying mechanism, the contents of the 7 major components of HGWD were determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The potential mechanism of HGWD in treating DCAN was predicted using network pharmacology combined with molecular docking and protein-protein docking. The diabetic rat model was induced using the high-fat diet (HFD) and streptozotocin (STZ) injection. After successful modeling, rats were pretreated with adeno-associated viral vectors containing transient receptor potential melastatin type 7 (TRPM7) recombinant plasmids (pAAV-TRPM7) for 4 weeks.

RESULTS

Clinical research showed that HGWD could reduce the number of ventricular premature beats, improve heart rate variability, and correct the imbalance of cardiac autonomic nerves in DCAN patients. In vivo experiments demonstrated that HGWD reduced susceptibility to arrhythmia, ameliorated diabetes-induced myocardial fibrosis, inhibited cardiac autonomic remodeling, and promoted repair of cardiac sympathetic nerves in diabetic rats. Mechanistically, HGWD had an ameliorative effect on DCAN by up-regulating the AMPK/TrkA (adenosine 5'-monophosphate-activated protein kinase/tyrosine kinase receptor A) pathway, thereby inhibiting the TRPM7 channel.

CONCLUSIONS

HGWD inhibited cardiac autonomic nervous system remodeling, reduced susceptibility to ventricular arrhythmias, and improved DCAN through the regulation of the AMPK/TrkA/TRPM7 pathway, which provided the strong support for its clinical application.