Diabetic cardiomyopathy (DCM) is one of the major chronic complications in diabetic patients. Conventional therapies for treatment of DCM include glycemic control, management of hypertension, lowering lipid and life-style management. However, there are no treatment strategies available that specifically target the pathogenesis of DCM. Greater understanding of the pathogenic mechanism of DCM is needed to develop improved therapeutic strategies. Stromal cell-derived factor-1 (SDF-1) belongs to C-X-C motif chemokine family. It controls diverse cell functions by interacting with its receptors, CXCR4 and CXCR7. Myocardial SDF-1 is transiently up-regulated during ischemia or after infarction and can attract stem cells to the injury site contributing to cardiac regeneration and angiogenesis. Exogenous SDF-1 can help prevent myocardial infarction and ischemia/reperfusion injury through stem cell-dependent and -independent mechanisms. However, the role and mechanism of the SDF-1-CXCR4/CXCR7 system in DCM has not been established. Accumulating evidence indicates that diabetes-induced deficiency of growth factors such as SDF-1 is associated with diabetic cardiovascular complications. In a preliminary study, the PI showed that the expression of SDF-1 is notably down-regulated in the cardiac tissue of mice with type 1 and type 2 diabetes, while the receptor expression levels are unaffected. The PI considered that lack of cardiac SDF-1 may contribute to DCM and supplementary SDF-1 may provide direct cardiomyocyte protection. As an initial test cultured cardiac cells were exposed to palmitate-mimicked diabetic lipotoxicity with SDF-1 pretreatment. These studies showed that SDF-1 protected against palmitate-induced cell death via CXCR7-, but not CXCR4-, mediated AMP-activated protein kinase (AMPK) activation. The results are of great significance since they demonstrate SDF-1 can provide direct protection against diabetic cardiac cell death independent of stem cells. Therefore, it is critical to determine if in vivo protection involves the same direct actions by SDF-1 identified on isolated cardiomyocytes. Based on the critical role of CXCR4 and CXCR7 in cardiovascular diseases, it is hypothesized that SDF-1 treatment of diabetic mice directly protects against diabetes-induced cardiomyocyte death and cardiac remodeling via CXCR7-mediated activation of AMPK and that SDF-1 treatment can ultimately prevent DCM. This hypothesis will be tested through three specific aims: (1) to determine the direct cardiomyocyte effects of SDF-1 in protection against DCM; (2) to determine whether SDF-1 signaling through CXCR7 mediates protection against DCM, independently of CXCR4; (3) to determine whether AMPK mediates SDF-1/CXCR7 protection against DCM. This project will provide fundamental evidence for the interaction of SDF-1-CXCR4 and/or -CXCR7 at the cardiomyocyte as a new therapeutic target for the prevention of DCM in future clinical investigations.
The objective of this study is to test our hypothesis that SDF-1 treatment of diabetic mice directly protects against diabetes-induced cardiomyocyte death and cardiac remodeling via CXCR7-mediated activation of AMPK and that SDF-1 treatment can ultimately prevent diabetic cardiomyopathy. We will first determine the direct cardiomyocyte effects of SDF-1 in protection against diabetic cardiomyopathy in type 2 diabetes. Next, we will determine which receptor mediates SDF-1's cardiomyocyte protection and the specific cell signaling pathway responsible. This project will reveal new insight into the underlying mechanism behind SDF-1 protection against diabetic cardiomyopathy as well as provide fundamental evidence supporting the SDF- 1/CXCR7 axis as a novel therapeutic target for the prevention of diabetic cardiomyopathy in future clinical practice.
| Gu, Junlian; Yan, Xiaoqing; Dai, Xiaozhen et al. (2018) Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts. Diabetes 67:507-517 |
