Abstract
Background: Diabetic cardiomyopathy (DCM) is characterized by cardiac fibrosis and stiffness, which often develops into heart failure. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. Methods: Forty-eight mice were divided into four groups (n = 12 per group): Group 1: Wild-type (WT) mice, Group 2: RasGRF1 deficiency (RasGRF1−/−) mice. Group 3: Streptozotocin (STZ)-induced diabetic WT mice, Group 4: STZ-induced diabetic RasGRF1−/− mice. Myocardial functions were assessed by cardiac echography. Heart tissues from all of the mice were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. Results: Worse impaired diastolic function with elevation serum interleukin (IL)-6 was found in the diabetic group compared with the non-diabetic groups. Serum IL-6 levels were found to be elevated in the diabetic compared with the non-diabetic groups. However, the diabetic RasGRF1−/− mice exhibited lower serum IL-6 levels and better diastolic function than the diabetic WT mice. The diabetic RasGRF1−/− mice were associated with reduced cardiac inflammation, which was shown by lower invading inflammation cells, lower expression of matrix metalloproteinase 9, and less chemokines compared to the diabetic WT mice. Furthermore, less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was also found in the diabetic RasGRF1−/− mice compared with the diabetic WT mice. Conclusion: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress.
Highlights
Multiple epidemiologic studies have reported a strong association between heart failure and diabetes mellitus (DM) [1,2,3]
The early phase of Diabetic cardiomyopathy (DCM) is characterized by symptoms of diastolic heart failure, which is caused by myocardial fibrosis via excess fibrotic processes, even without the loss of cardiomyocytes [7,8,9]
Myocardial fibrosis is a hallmark of heart disease, and is defined as an abnormal deposition of collagen, fibronectin, and other extracellular matrices, which leads to increased myocardial stiffness and consequent cardiac dysfunction, resulting in heart failure [10,11,12,13]
Summary
Multiple epidemiologic studies have reported a strong association between heart failure and diabetes mellitus (DM) [1,2,3]. Streptozotocin (STZ)-induced diabetic mice with impaired diastolic function, heart failure, and exhibiting features of cardiac hypertrophy, myofibril depletion, and interstitial fibrosis were developed, and are used to study the mechanism of DCM [6,7,14,15]. This study investigated the role of RasGRF1 in heart failure induced by chronic diabetes. This study investigated the role of Ras protein-specific guanine nucleotide releasing factor 1 (RasGRF1) in the development of DCM. Less oxidative stress as well as extracellular matrix deposition leading to a reduction in cardiac fibrosis was found in the diabetic RasGRF1−/− mice compared with the diabetic WT mice. Conclusion: The deletion of RasGRF1 attenuated myocardial fibrosis and improved cardiac function in diabetic mice through inhibiting inflammation and oxidative stress
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