br Conflicts of interest br Research
Conflicts of interest
Research involving humans
Research involving animals
Acknowledgements This work was supported in part by National Institute of Health [grant numbers AG030539, AG044817, AG051266, NS050276, and RR027990], the Alzheimer's Association (ZEN-14-283969), the BrightFocus Foundation (A2015275S), and grants supporting the Brain and Body Donation Program of the Banner Sun Health Research Institute [NIH AG19610 and NS072026, the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and The Michael J. Fox Foundation for Parkinson's Research].
Introduction Cardiovascular complications are the principal cause of morbidity and mortality among the diabetic population , . Diabetic cardiomyopathy (DCM) has attracted much attention due to its complex pathophysiology and increased mortality . As the main clinical manifestation of diabetes, hyperglycemia has been found to cause numerous alterations and ultimately leads to DCM . The multifaceted mechanisms of DCM involve elevated oxidative stress , , cardiac inflammatory responses , , cardiomyocyte apoptosis  and myocardial remodeling . Inflammatory responses and oxidative stress seem to be upstream of these signaling cascades. Oxidative stress and inflammatory responses have been shown to cross-talk and interact with each other . Thus, the inhibition of oxidative stress and inflammation is of great importance to the treatment of DCM . Klotho is an anti-aging protein that is predominantly expressed in the kidney . A circulating form of Klotho, named soluble Klotho (derived from proteolytic cleavage of the transmembrane protein), is detectable in the circulation and acts as a humoral factor. Klotho has been found to regulate Sotrastaurin (AEB071) metabolism and stress resistance, exert antioxidative and anti-inflammatory effects, and modulate calcium and mineral homeostasis , , , . Previous studies have demonstrated that Klotho inhibits the production of the pro-inflammatory cytokine IL-6 in endothelial cells . In addition, Klotho is an anti-inflammatory modulator in the kidney . These data indicate that Klotho plays an essential role in inflammation and oxidative stress, both of which are linked to the pathogenesis of DCM. Interestingly, Klotho-deficient (kl/+) mice exhibit similar phenotypic features to cardiovascular disease (CVD) patients, including accelerated left ventricular hypertrophy (LVH), vascular calcification and early death , , , . Therefore, more attention has been paid to the relationship between Klotho and cardiovascular disease. Haipeng Hui et al.  recently reported that Klotho could ameliorate aging-related inflammatory responses and cardiac dysfunction in endotoxemic mice. Klotho has been shown to exert a protective effect on cardiomyocytes by inhibiting TRPC6 channels . Despite these findings, the role of Klotho in DCM remains unknown, though elevated inflammation and oxidative stress are closely related to this disease.
Materials and methods
Discussion Considerable evidence suggests that enhanced inflammation and oxidative stress accompanied by the activation of cell death pathways and fibrosis play key roles in the pathogenesis of DCM . In accordance with previous studies, the development of DCM in the STZ-induced diabetic mouse model used in our study was characterized by various cardiac histological abnormalities coupled with accelerated cardiac inflammation, oxidative stress, fibrosis, hypertrophy and cell death (Fig. 5, Fig. 6, Fig. 7). Similar results were also observed in H9c2 cells and neonatal cardiomyocytes exposed to HG (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. S1, Fig. S2, Fig. S3, Fig. S4, Fig. S5). However, despite the evidence that has been obtained in recent decades, DCM treatment remains ineffective.