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Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes.

ABSTRACT: Aims: To evaluate the protective effects of exogenous pancreatic kallikrein (PKK) treatment on diabetic cardiomyopathy (DCM) and explore the underlying mechanisms. Methods and Results: Streptozotocin (STZ)-induced diabetic rats, a type 1 diabetic model, were treated with either PKK or saline for 12 weeks. Non-diabetic rats were used as controls. PKK administration attenuated the mitochondria swelling, Z line misalignments, myofibrosis and interstitial collagen accumulation in diabetic myocardial tissue. The oxidative stress imbalance including increased nitrotyrosine, decreased anti-oxidative components such as nuclear receptor nuclear factor like 2 (Nrf2), glutathione peroxidase 1(GPx-1), catalase (CAT) and superoxide dismutase (SOD), were recovered in the heart of PKK-treated diabetic rats. In diabetic rats, protein expression of TGF-?1 and accumulation of collagen I in the heart tissues was decreased after PKK administration. Markers for inflammation were decreased in diabetic rats by PKK treatment. Compared to diabetic rats, PKK reversed the degradation of I?B-?, an inhibitive element of heterotrimer nuclear factor kappa B (NF-?B). The endothelial nitric oxide synthase (eNOS) protein and myocardial nitrate/nitrite were impaired in the heart of diabetic rats, which, however, were restored after PKK treatment. The sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and phospholamban (PLN) were mishandled in diabetic rats, while were rectified in PKK-treated diabetic rats. The plasma NT-proBNP level was increased in diabetic rats while was reduced with PKK treatment. Conclusion: PKK protects against DCM via reducing fibrosis, inflammation, and oxidative stress, promoting nitric oxide production, as well as restoring the function of the calcium channel.

SUBMITTER: Wu M

PROVIDER: S-EPMC6091235 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes.

Wu Meng M Yang Yeping Y Wang Meng M Zeng Fangfang F Li Qin Q Liu Wenjuan W Guo Shizhe S He Min M Wang Yi Y Huang Jie J Zhou Linuo L Li Yiming Y Hu Ji J Gong Wei W Zhang Zhaoyun Z

Frontiers in pharmacology 20180807

<b>Aims:</b> To evaluate the protective effects of exogenous pancreatic kallikrein (PKK) treatment on diabetic cardiomyopathy (DCM) and explore the underlying mechanisms. <b>Methods and Results:</b> Streptozotocin (STZ)-induced diabetic rats, a type 1 diabetic model, were treated with either PKK or saline for 12 weeks. Non-diabetic rats were used as controls. PKK administration attenuated the mitochondria swelling, Z line misalignments, myofibrosis and interstitial collagen accumulation in diabe ...[more]

PMID: 30131697

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Project description:Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active cis-epoxyeicosatrienoic acids, which have potent vasodilatory, antiinflammatory, antiapoptotic, and antidiabetes properties. Here, we showed the effects of cardiac-specific overexpression of CYP epoxygenase 2J2 (CYP2J2) on diabetic cardiomyopathy and insulin resistance in high-fat (HF) diet fed, low-dose streptozotocin-treated mice. Diabetic cardiomyopathy was induced by HF and streptozotocin in cardiac-specific CYP2J2 transgenic mice. Physiological parameters and systemic metabolic parameters were monitored using ELISA kits. Intraperitoneal injection glucose tolerance test and hyperinsulinemic-euglycemic clamp study were implied to indicate insulin resistance. Cardiac function was assessed by echocardiography and Millar catheter system. Real-time PCR and Western blotting were used in signal pathway detection. αMHC-CYP2J2 transgenic mice showed significantly lower plasma glucose and insulin levels, improved glucose tolerance, and increased cardiac glucose uptake. Furthermore, αMHC-CYP2J2 transgenic mice were significantly protected from HF-streptozotocin-induced diabetic cardiomyopathy. Strikingly, CYP2J2 overexpression attenuated myocardial hypertrophy induced by diabetes. We conclude that cardiac-specific overexpression of CYP2J2 significantly protects against diabetic cardiomyopathy, which may be due to improved cardiac insulin resistance, glucose uptake, and reversal of cardiac hypertrophy. Relevant mechanisms may include up-regulation of peroxisome proliferator-activated receptor γ, activation of insulin receptor and AMP-activated protein kinase signaling pathways, and inhibition of nuclear factor of activated T cells c3 signal by enhanced atrial natriuretic peptide production. These results suggest that CYP2J2 epoxygenase metabolites likely play an important role in plasma glucose homeostasis, and enhancement of epoxyeicosatrienoic acids activation may serve as an effective therapeutic strategy to prevent diabetic cardiomyopathy.

Dataset Information

Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes.

Publications

Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes.

Similar Datasets

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