Carvacrol protects against diabetes-induced hypercontractility in the aorta through activation of the PI3K/Akt pathway.

Vascular complications induced by diabetes constitute the principal cause of morbidity and mortality in diabetic patients. It has been reported that carvacrol (CAR) possesses a wide range of biological activities. The effects of CAR on diabetes-induced vasculopathy remain unknown. In this study, diabetic mice were created by the intraperitoneal injection of streptozotocin (STZ) in male C57BL/6 J mice to investigate whether CAR provided a protective effect against diabetes-induced vasculopathy and to investigate the underlying mechanisms. We found that CAR decreased blood glucose levels in diabetic mice. Moreover, CAR ameliorated diabetes-induced aortic morphological alterations, as evidenced by an increased thickness in the intima-media width and an increased number of vascular smooth muscle cells (VSMCs) layers. Further studies revealed that CAR inhibited hypercontractility in the aortas of diabetic mice and VSMCs in response to hyperglycemia, as evidenced by the relaxation of phenylephrine(PE)-induced vasoconstriction, the decreased expression of smooth muscle (SM)-α-actin, and the increased expression of Ki67 and proliferating cell nuclear antigen (PCNA). Furthermore, the PI3K/Akt signaling pathway was inhibited in the aortas of diabetic mice and VSMCs in response to hyperglycemia, while CAR treatment activated the PI3K/Akt signaling pathway. In conclusion, our results strongly suggest that CAR plays a protective role in diabetes-induced aortic hypercontractility, possibly by activating the PI3K/Akt signaling pathway. CAR is a potential drug for the treatment of diabetic vasculopathy.

Contributions of Nrf2 to Puerarin Prevention of Cardiac Hypertrophy and its Metabolic Enzymes Expression in Rats.

Previous evidence has suggested that puerarin may attenuate cardiac hypertrophy; however, the potential mechanisms have not been determined. Moreover, the use of puerarin is limited by severe adverse events, including intravascular hemolysis. This study used a rat model of abdominal aortic constriction (AAC)-induced cardiac hypertrophy to evaluate the potential mechanisms underlying the attenuating efficacy of puerarin on cardiac hypertrophy, as well as the metabolic mechanisms of puerarin involved. We confirmed that puerarin (50 mg/kg per day) significantly attenuated cardiac hypertrophy, upregulated Nrf2, and decreased Keap1 in the myocardium. Moreover, puerarin significantly promoted Nrf2 nuclear accumulation in parallel with the upregulated downstream proteins, including heme oxygenase 1, glutathione transferase P1, and NAD(P)H:quinone oxidoreductase 1. Similar results were obtained in neonatal rat cardiomyocytes (NRCMs) treated with angiotensin II (Ang II; 1 µM) and puerarin (100 µM), whereas the silencing of Nrf2 abolished the antihypertrophic effects of puerarin. The mRNA and protein levels of UGT1A1 and UGT1A9, enzymes for puerarin metabolism, were significantly increased in the liver and heart tissues of AAC rats and Ang II-treated NRCMs. Interestingly, the silencing of Nrf2 attenuated the puerarin-induced upregulation of UGT1A1 and UGT1A9. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction indicated that the binding of Nrf2 to the promoter region of Ugt1a1 or Ugt1a9 was significantly enhanced in puerarin-treated cardiomyocytes. These results suggest that Nrf2 is the key regulator of antihypertrophic effects and upregulation of the metabolic enzymes UGT1A1 and UGT1A9 of puerarin. The autoregulatory circuits between puerarin and Nrf2-induced UGT1A1/1A9 are beneficial to attenuate adverse effects and maintain the pharmacologic effects of puerarin.