Sarcolipin acts as a bridge between diabetes and heart failure.

Diabetes mellitus and heart failure are common conditions, particularly in older adults, and each condition is associated with heightened morbidity and mortality. It is well established that diabetes amplifies the risk for the development of heart failure, independent of co‐morbid conditions such as hypertension and obesity. Importantly, the coexistence of diabetes and heart failure is associated with significantly worsened morbidity and mortality compared to patients with heart failure without diabetes. However, the detailed molecular mechanisms underlying this process remain elusive.

Recently, Liu et al. uncovered a key role of sarcolipin (SLN) in mediating the exacerbation of heart failure by diabetes mellitus, which was published in the latest issue of ESC Heart Failure. SLN is an inhibitor of sarcoplasmic reticulum calcium‐ATPase (SERCA), which handles intracellular calcium reuptake and plays a critical role in heart failure. In this study, the author evaluated molecular changes in a rat model with STZ‐induced diabetes for 16 weeks, followed by myocardial infarction (MI) by left anterior descending coronary artery ligation. The author found that STZ‐induced diabetes up‐regulated SLN mRNA level and protein level in a time‐dependent manner, which is associated with reduced expression of DNA methyltransferases (DNMTs) and decreased methylation rate in the promoter of SLN gene, suggesting the involvement of epigenetic mechanism underlying the regulation of SLN expression in diabetes. Besides, diabetes resulted in a greater reduction in the activity of SERCA2a, coupled with worse ventricular function in MI heart compared to that in MI group without diabetes. Interestingly, depletion of SLN by AAV9‐shRNA in heart recovered SERCA2a activity and improved left ventricular systolic dysfunction in the diabetic MI rat model. It was noted that the protein level of SLN expression was not changed in MI heart and depletion of SLN has no effects on SERCA2a activity and cardiac dysfunction in this group. Importantly, the expression of SLN was also evaluated in human cardiac tissue from STEMI patients who exhibited impaired cardiac systolic function with diabetes and non‐diabetes. Consistent with the finding from the animal experiments, SLN expression was significantly up‐regulated in diabetic heart compared with non‐diabetic hearts. Collectively, these results demonstrated a critical role of SLN in mediating the deterioration of heart failure in diabetic setting.

Taken together, this study uncovered a new mechanism underlying the deterioration of heart failure patients with diabetes and highlighted a key pathogenic role of SLN in mediating high‐glucose‐induced cardiac contraction dysfunction. Therefore, targeting SLN may have therapeutic potential in treating heart failure patients with diabetes.

Funding

This work was supported by the financial support from Wuhan University (Grant Number 2042019kf0074) and from the Second Affiliated Hospital of University of South China (Grant number: 2018B02).