Effect of RAGE Manipulation on Diabetic Cardiomyopathy in Mice

Abstract

Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in the development of many ailments including diabetes. Soluble RAGE (sRAGE), which acts as a decoy of RAGE, has been studied as a potential therapeutic agent against vascular complications of diabetes. Here we tested the effects of RAGE manipulation in vivo on diabetic cardiomyopathy. We have reported that genetic over-expression of sRAGE produces a consistent high level of plasma sRAGE in mice. In this study, we created a mouse model that has over-expressed sRAGE with either intact or knocked-out RAGE. Diabetes was induced by STZ in following mice with: (1) over-expressed sRAGE and intact RAGE (S group); (2) over-expressed sRAGE and knocked-out RAGE (D group); and (3) wildtypes that have a normal expression of both sRAGE and RAGE (C group). During the 4-month of post-STZ injection, cardiovascular morphology and function were studied using serial Echocardiography, end-point invasive hemodynamic measurements and pathological analysis. A severe hyperglycemia was observed throughout the experiment in all diabetic mice. As expected, a significant reduction of bodyweight, heart weight, heart rate, left ventricular (LV) systolic parameters, LV diastolic parameters, LV Ejection fraction (EF), vascular functional parameters and survival rate (33%) were observed in C group, as indications of diabetic cardiomyopathy, compared to non-diabetic counterparts. Interestingly, in S group, those parameters were identical to that in C group (30% of survival rate in S group). However, in D group, while the effects of hyperglycemia on bodyweight and LV diastolic parameters were similar to that in C and S groups, there was a significantly better survival rate (70%; p<0.05), better LV systolic parameters, better EF and better vascular functional parameters, and lesser reduction in heart weight and heart rate compared to that in C and S groups (Figure). Our results suggested that manipulation of RAGE signaling attenuates the development of diabetic cardiomyopathy. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in the development of many ailments including diabetes. Soluble RAGE (sRAGE), which acts as a decoy of RAGE, has been studied as a potential therapeutic agent against vascular complications of diabetes. Here we tested the effects of RAGE manipulation in vivo on diabetic cardiomyopathy. We have reported that genetic over-expression of sRAGE produces a consistent high level of plasma sRAGE in mice. In this study, we created a mouse model that has over-expressed sRAGE with either intact or knocked-out RAGE. Diabetes was induced by STZ in following mice with: (1) over-expressed sRAGE and intact RAGE (S group); (2) over-expressed sRAGE and knocked-out RAGE (D group); and (3) wildtypes that have a normal expression of both sRAGE and RAGE (C group). During the 4-month of post-STZ injection, cardiovascular morphology and function were studied using serial Echocardiography, end-point invasive hemodynamic measurements and pathological analysis. A severe hyperglycemia was observed throughout the experiment in all diabetic mice. As expected, a significant reduction of bodyweight, heart weight, heart rate, left ventricular (LV) systolic parameters, LV diastolic parameters, LV Ejection fraction (EF), vascular functional parameters and survival rate (33%) were observed in C group, as indications of diabetic cardiomyopathy, compared to non-diabetic counterparts. Interestingly, in S group, those parameters were identical to that in C group (30% of survival rate in S group). However, in D group, while the effects of hyperglycemia on bodyweight and LV diastolic parameters were similar to that in C and S groups, there was a significantly better survival rate (70%; p<0.05), better LV systolic parameters, better EF and better vascular functional parameters, and lesser reduction in heart weight and heart rate compared to that in C and S groups (Figure). Our results suggested that manipulation of RAGE signaling attenuates the development of diabetic cardiomyopathy.