Higenamine Hydrochloride Ameliorates Diabetic Cardiomyopathy Through RhoA/MEK/ERK Pathway

Diabetic cardiomyopathy (DCM) is a major complication of diabetes, characterized by myocardial inflammation, oxidative stress, fibrosis, apoptosis, and RhoA activation, ultimately leading to heart failure. This study aimed to evaluate whether higenamine hydrochloride (HGN), a natural alkaloid with anti-inflammatory and antioxidant properties, could alleviate DCM and elucidate its underlying mechanisms. A DCM model was established via streptozotocin injection in mice, followed by HGN administration. Fasudil, a RhoA inhibitor, was used to assess pathway involvement. Histology, biochemical assays, flow cytometry, immunoblotting, ELISA, and qPCR were employed for evaluation. Results showed that HGN effectively alleviated cardiac histological abnormalities and myocardial injury in DCM mice. Further analysis revealed that HGN attenuated DCM-induced cardiac inflammation, oxidative stress, fibrosis, and apoptosis (p < 0.05). In vitro, HGN also reduced high glucose-induced inflammation, oxidative stress, fibrosis, and apoptosis in H9C2 cardiomyocytes (p < 0.05). Mechanistically, these protective effects were mediated by inhibition of RhoA, through which HGN suppressed the MEK/ERK signalling pathway, thereby mitigating cardiomyocyte injury (p < 0.05). However, the RhoA inhibitor fasudil hydrochloride abolished the cardioprotective effects of HGN in DCM mice, specifically, fasudil hydrochloride reversed the HGN-induced improvements in cTnT, CK, and LDH levels. Additionally, echocardiographic parameters (IVSD, LVPWd, LVPWs, LVIDd, LVIDs, IVSs, EF, and FS) were also reversed to levels seen in untreated DCM mice, further confirming that HGN exerts its therapeutic actions via the RhoA/MEK/ERK axis (p < 0.05). Overall, HGN mitigates cardiac inflammation, oxidative stress, fibrosis, and apoptosis in DCM by inhibiting the MEK/ERK pathway through RhoA. This study provides a scientific basis for developing DCM treatments and highlights the therapeutic potential of HGN.