, a major active component of ginseng, has many benefits for cardiovascular disease and diabetes mellitus (DM), but the effect and mechanism on diabetic cardiomyopathy are not clear. In the present study, we found that Rb1-feeding significantly improved cardiac dysfunction and abnormal cardiomyocytes calcium signaling caused by diabetes. This improved calcium signaling was because Rb1 reduced Ca 2+ leakage caused by overactivated ryanodine receptor 2 (RyR2) and increased Ca 2+ uptake by sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA 2a). Furthermore, we found that Rb1 not only enhanced energy metabolism like metformin and eliminated O-GlcNAcylation of calcium handling proteins to regulate calcium signaling but also directly inhibited RyR2 activity to regulate calcium signaling. The present study indicated that as a health supplement or drug, Rb1 was a relatively effective auxiliary therapeutic substance for diabetic cardiomyopathy.

Scope Hyperglycemia‐induced cardiac fibrosis is one of the main causes of diabetic cardiomyopathy (DM). Chlorogenic acid (CGA) found in many foods has excellent hypoglycemic effectiveness, but it is not known whether CGA can improve DM by inhibiting cardiac fibrosis caused by hyperglycemia. Methods and Results Type I diabetic mice are induced by streptozotocin, and after treatment with CGA for 12 weeks, cardiac functions and fibrosis are determined. CGA significantly attenuates hyperglycemia‐induced cardiac fibrosis and improves cardiac functions. The mechanism of CGA on fibrotic inhibition is further studied by immunofluorescence, western blot and RNA interference technology in vivo and in vitro. The results show CGA exerted its anti‐fibrotic effects through activating the cyclic GMP/protein kinase G pathway (cGMP/PKG) to block hyperglycemia‐induced nuclear translocation of p‐Smad2/3, and then inhibiting pro‐fibrotic gene expression in cardiac fibroblasts without depending on its hypoglycemic function. Moreover, the data also revealed that CGA increased cGMP level and activated PKG in cardiac fibroblasts by enhancing endothelial nitric oxide synthase (eNOS) activity and NO production. Conclusion Besides lowering blood glucose, CGA also has an independent ability to inhibit cardiac fibrosis. Therefore, long‐term consumption of foods rich in CGA for diabetic patients will have great benefits to improve diabetic cardiomyopathy.

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