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Cardioprotective Effect of Decorin in Type 2 Diabetes.

ABSTRACT: Cardiomyopathy is the leading cause of increased mortality in diabetes. In the present study, we investigated the effects of decorin (DCN) gene therapy on left ventricular function, cardiac inflammation and fibrosis in type 2 diabetes. Type 2 diabetes was induced in male Wistar rats by high fat diet (HFD, 60% of calories as fat) and STZ (20 mg/kg, intraperitoneal). Diabetic rats were divided into (n=6 for each group) the control group, the GFP-treated group and the DCN-treated group, received intravenous injection of saline solution, recombinant adeno-associated viral (rAAV)-GFP, and rAAV-DCN, respectively. We evaluated cardiac inflammation, fibrosis, left ventricular function at 6 months after gene delivery. Results turned out that rAAV-DCN treatment attenuated diabetic cardiomyopathy with improved LV function compared with control animals, which might be related to the reduced cardiac inflammation and fibrosis. These protective effects were associated with TGF?1 pathway (ERK1/2 and smad-2) and NF-?B pathway, which may due to the decreased activation level of IGF-IR, increased expression of PKC-? and Hsp70. In conclusion, our results show that rAAV-mediated DCN therapy may be beneficial in the treatment of Diabetic Cardiomyopathy.

SUBMITTER: Chen F

PROVIDER: S-EPMC7750479 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cardioprotective Effect of Decorin in Type 2 Diabetes.

Chen Fuqiong F Lai Jinsheng J Zhu Yanfang Y He Mengying M Hou Huiying H Wang Jin J Chen Chen C Wang Dao Wen DW Tang Jiarong J

Frontiers in endocrinology 20201207

Cardiomyopathy is the leading cause of increased mortality in diabetes. In the present study, we investigated the effects of decorin (DCN) gene therapy on left ventricular function, cardiac inflammation and fibrosis in type 2 diabetes. Type 2 diabetes was induced in male Wistar rats by high fat diet (HFD, 60% of calories as fat) and STZ (20 mg/kg, intraperitoneal). Diabetic rats were divided into (n=6 for each group) the control group, the GFP-treated group and the DCN-treated group, received in ...[more]

PMID: 33365011

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Project description:Decorin, a small leucine-rich proteoglycan, regulates extracellular matrix organization, growth factor-mediated signaling, and cell growth. Because decorin may directly modulate immune responses, we investigated its role in a mouse model of contact allergy (oxazolone-mediated delayed-type hypersensitivity [DTH]) in decorin-deficient (Dcn(-/-)) and wild-type mice. Dcn(-/-) mice showed a reduced ear swelling 24 h after oxazolone treatment with a concurrent attenuation of leukocyte infiltration. These findings were corroborated by reduced glucose metabolism, as determined by (18)fluordeoxyglucose uptake in positron emission tomography scans. Unexpectedly, polymorphonuclear leukocyte numbers in Dcn(-/-) blood vessels were significantly increased and accompanied by large numbers of flattened leukocytes adherent to the endothelium. Intravital microscopy and flow chamber and static adhesion assays confirmed increased adhesion and reduced transmigration of Dcn(-/-) leukocytes. Circulating blood neutrophil numbers were significantly increased in Dcn(-/-) mice 24 h after DTH elicitation, but they were only moderately increased in wild-type mice. Expression of the proinflammatory cytokine TNF-? was reduced, whereas syndecan-1 and ICAM-1 were overexpressed in inflamed ears of Dcn(-/-) mice, indicating that these adhesion molecules could be responsible for increased leukocyte adhesion. Decorin treatment of endothelial cells increased tyrosine phosphorylation and reduced syndecan-1 expression. Notably, absence of syndecan-1 in a genetic background lacking decorin rescued the attenuated DTH phenotype of Dcn(-/-) mice. Collectively, these results implicated a role for decorin in mediating DTH responses by influencing polymorphonuclear leukocyte attachment to the endothelium. This occurs via two nonmutually exclusive mechanisms that involve a direct antiadhesive effect on polymorphonuclear leukocytes and a negative regulation of ICAM-1 and syndecan-1 expression.

Project description:Background SGLT-2 (sodium glucose transporter-2) inhibitors and GLP-1RAs (glucagon-like peptide-1 receptor agonists) effectively lowered cardiovascular risk in large clinical trials for patients with type 2 diabetes mellitus at high risk for these complications, and have been recommended by guidelines. To evaluate the contemporary landscape in which these recommendations would be implemented, we examined the use of these medications according to clinical guideline practice. Methods and Results In the National Health and Nutrition Examination Survey for 2017 to 2018, we defined compelling indications for SGLT-2 inhibitors by the presence of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, and for GLP-1RAs by the presence of established or high-risk atherosclerotic cardiovascular disease, based on large clinical trials that have been incorporated in guideline recommendations of the American College of Cardiology and American Diabetes Association. We then evaluated use of these medications among patients with physician-diagnosed type 2 diabetes mellitus. All analyses incorporated complex survey design to produce nationally representative estimates. A total 1104 of 9254 sampled individuals had type 2 diabetes mellitus, representing 10.6% (95% CI, 9.7%-11.6%) of the US population or 33.2 million adults nationally. Of these, 52.6% (95% CI, 47.7%-57.5%) had an indication for SGLT-2 inhibitors, 32.8% (95% CI, 28.8%-37.2%) for GLP-1RAs, and 26.6% (95% CI, 22.2%-31.7%) for both medications. During 2017 to 2018, 4.5% (95% CI, 2.4%-8.2%) were treated with SGLT-2 inhibitors and 1.5% (95% CI, 0.7%-3.2%) with GLP-1RAs. Atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease were not independently associated with SGLT-2 inhibitor or GLP-1RA use in patients with diabetes mellitus. Conclusions Despite a large number of patients being eligible for guideline-recommended cardiorenal protective therapies, there are substantial gaps in the use of SGLT-2 inhibitors and GLP-1RAs, limiting their public health benefits.

Project description:We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

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Cardioprotective Effect of Decorin in Type 2 Diabetes.

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Cardioprotective Effect of Decorin in Type 2 Diabetes.

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