Rhynchophylline Regulates Calcium Homeostasis by Antagonizing Ryanodine Receptor 2 Phosphorylation to Improve Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that can lead to heart failure and death, for which there is no effective treatment. Rhynchophylline (Rhy) is the main effective component of the Chinese herbal medicine Uncaria rhynchophylla, which mainly acts on the cardiovascular and nervous systems. However, its role in protecting against DCM remains unexplored. The present study sought to reveal the mechanism of Rhy in improving type 2 diabetes mellitus (T2DM) myocardial lesions from the perspective of regulating calcium homeostasis in cardiomyocytes. We prepared a mouse model of T2DM using a high-fat diet combined with low doses of streptozotocin. The T2DM mice were given 40 mg/kg of Rhy for 8 weeks. The results showed that Rhy can attenuate cardiac pathological changes, slow down the heart rate, decrease serum cardiac enzyme levels, reduce cardiomyocyte apoptosis, enhance cardiomyocyte contractility, and raise the calcium transient amplitude in T2DM mice. Further, Rhy downregulated the phosphorylation level of ryanodine receptor 2, upregulated the phosphorylation level of phospholamban, protected mitochondrial structure and function, and increased adenosine triphosphate levels in the cardiac tissue of T2DM mice. Our results demonstrated that Rhy may protect against myocardial damage in T2DM mice and promote cardiomyocyte contraction, and its mechanism of action seems to be related to the regulation of intracellular calcium homeostasis.

Post‐translational modifications in diabetic cardiomyopathy

“…Molecular insights implicated that Rhy can inhibit the overactivation of the sarcoplasmic reticulum Ryanodine receptor 2 (RyR2), which was known to cause increased Ca 2+ leakage. This inhibition was primarily achieved by antagonizing RyR2 phosphorylation thereby regulating calcium homeostasis 51 (Figure 3 ). As mentioned previously, CaMKII Ser280 can be activated by O‐GlcNAcylation to release Ca 2+ and, in addition, CaMKII can be activated by phosphorylation 52 (Figure 3 ).…”

Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects

“…Myocardial calcium homeostasis, which plays an important role in myocardial contractility, is disturbed in diabetic cardiomyopathy [55]. Physiologically, calcium released into the cytoplasm from the sarcoplasmic reticulum is returned to the sarcoplasmic reticulum by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a).…”

“…More studies must be executed to further investigate the impacts of trientine on myocardial calcium regulation. The role of calcium-modulating proteins such as ryanodine receptor type 2 (RyR2) and FOK-binding protein/calstabin 2 (FKBP12.6), which are involved in calcium release, or phospholamban in calcium uptake [55,58] could be examined. Possible effects of trientine on calsequestrin 2 (CASQ2), which is responsible for calcium storage [59], should also be studied.…”