Phosphoinositide 3-Kinase p110alpha Gene Therapy Rescues Diabetic Cardiomyopathy in a Type 2 Diabetic Model

Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly, the more prevalent type 2 diabetes patient population. In the current study, we investigated whether administration of recombinant adeno-associated viral vectors carrying a constitutively active phosphoinositide 3-kinase (PI3K)(p110α) construct (rAAV6-caPI3K) at a clinically relevant time point attenuates diabetic cardiomyopathy in a preclinical type 2 diabetes (T2D) model. T2D was induced by a combination of a high-fat diet (42% energy intake from lipid) and low-dose streptozotocin (three consecutive intraperitoneal injections of 55 mg/kg body wt), and confirmed by increased body weight, mild hyperglycemia, and impaired glucose tolerance (all P < 0.05 vs. nondiabetic mice). After 18 wk of untreated diabetes, impaired left ventricular (LV) systolic dysfunction was evident, as confirmed by reduced fractional shortening and velocity of circumferential fiber shortening (Vcfc, all P < 0.01 vs. baseline measurement). A single tail vein injection of rAAV6-caPI3K gene therapy (2×1011vector genomes) was then administered. Mice were followed for an additional 8 wk before end point. A single injection of cardiac targeted rAAV6-caPI3K attenuated diabetes-induced cardiac remodeling by limiting cardiac fibrosis (reduced interstitial and perivascular collagen deposition, P < 0.01 vs. T2D mice) and cardiomyocyte hypertrophy (reduced cardiomyocyte size and Nppa gene expression, P < 0.001 and P < 0.05 vs. T2D mice, respectively). The diabetes-induced LV systolic dysfunction was reversed with rAAV6-caPI3K, as demonstrated by improved fractional shortening and velocity of circumferential fiber shortening (all P < 0.05 vs pre-AAV measurement). This cardioprotection occurred in combination with reduced LV reactive oxygen species ( P < 0.05 vs. T2D mice) and an associated decrease in markers of endoplasmic reticulum stress (reduced Grp94 and Chop, all P < 0.05 vs. T2D mice). Together, our findings demonstrate that a cardiac-selective increase in PI3K(p110α), via rAAV6-caPI3K, attenuates T2D-induced diabetic cardiomyopathy, providing proof of concept for potential translation to the clinic. NEW & NOTEWORTHY Diabetes remains a major cause of death and disability worldwide (and its resultant heart failure burden), despite current care. The lack of existing management of heart failure in the context of the poorer prognosis of concomitant diabetes represents an unmet clinical need. In the present study, we now demonstrate that delayed intervention with PI3K gene therapy (rAAV6-caPI3K), administered as a single dose in mice with preexisting type 2 diabetes, attenuates several characteristics of diabetic cardiomyopathy, including diabetes-induced impairments in cardiac remodeling, oxidative stress, and function. Our discovery here contributes to the previous body of work, suggesting the cardioprotective effects of PI3K(p110α) could be a novel therapeutic approach to reduce the progression to heart failure and death in diabetes-affected patients.

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Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200420084444 ◽

2020 ◽

Vol 20 (7) ◽

pp. 1117-1132

Author(s):

Abdelaziz M. Hussein ◽

Elsayed A. Eid ◽

Ismaeel Bin-Jaliah ◽

Medhat Taha ◽

Lashin S. Lashin

Keyword(s):

Oxidative Stress ◽

Blood Glucose ◽

Diabetic Cardiomyopathy ◽

Caspase 3 ◽

Stevia Rebaudiana ◽

Diabetic Rats ◽

Control Group ◽

Underlying Mechanisms ◽

Type 2 Diabetic

Background and Aims: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms. Methods: : Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured. Results: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05). Conclusion: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

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Angiotensin II causes endothelial dysfunction via the GRK2/Akt/eNOS pathway in aortas from a murine type 2 diabetic model

Pharmacological Research ◽

10.1016/j.phrs.2011.05.001 ◽

2011 ◽

Vol 64 (5) ◽

pp. 535-546 ◽

Cited By ~ 34

Author(s):

Kumiko Taguchi ◽

Tsuneo Kobayashi ◽

Yasuhiro Takenouchi ◽

Takayuki Matsumoto ◽

Katsuo Kamata

Keyword(s):

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Diabetic Model ◽

Type 2 Diabetic

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Antidiabetic effect of enterolactone in cultured muscle cells and in type 2 diabetic model db/db mice

Cytotechnology ◽

10.1007/s10616-016-9965-2 ◽

2016 ◽

Vol 69 (3) ◽

pp. 493-502 ◽

Cited By ~ 8

Author(s):

Fang Zhou ◽

Keisuke Furuhashi ◽

Myoung Jin Son ◽

Miku Toyozaki ◽

Fumiaki Yoshizawa ◽

...

Keyword(s):

Muscle Cells ◽

Antidiabetic Effect ◽

Diabetic Model ◽

Type 2 Diabetic

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Comparative Study on Antidiabetic Effect of Ethanolic Extract of Jute Leaf on Neonatal Streptozotocin- Induced Type-2 Diabetic Model Rat

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i3130922 ◽

2020 ◽

pp. 60-71

Author(s):

Md. Mahabub Ali ◽

Md. Asrafuzzaman ◽

Md. Mahedi Hassan Tusher ◽

Md. Hafizur Rahman ◽

Md. Tanvir Rahman ◽

...

Keyword(s):

Body Weight ◽

Lipid Profile ◽

Ethanolic Extract ◽

Liver Glycogen ◽

Serum Glucose ◽

Water Control ◽

Citrate Buffer ◽

Diabetic Model ◽

Type 2 Diabetic

Aim: Functional food and their bioactive compounds have been considered as a new approach for the prevention and management of type 2 diabetes and its complications. According to this approach current study was carried out as an elucidation of antidiabetic properties of Corchorus capsularis and Corchorus olitorius varieties of jute leaf (ethanolic extract) on nSTZ-induced type-2 diabetic rats. Methodology: The type-2 diabetic model rat was developed by a single intraperitoneal injection of freshly prepared STZ (90 mg/kg/10 ml) in sterile citrate buffer (0.1 M, pH 4.5) to rat pups (48 hour old). After three months, OGTT was performed to select diabetic (FSG > 6.5mmol/L and after 90 min of glucose load > 14 mmol/L) experimental rats. The rats were randomly divided into four groups [DWC, GT, Ext-1 and Ext-2 represent, diabetic water control, glybenclamide treated (20 mg/5 ml/kg body weight), C. capsularis treated and C. olitorius treated group (1.25 g/10 ml/kg body weight) respectively]. One group was kept with normal rats [normal water control, NWC]. The treatment was given once daily or 28 consecutive days. Fasting serum glucose, liver glycogen and lipid profile were estimated by using standard methods. Results: The results showed that Ext-1 and Ext-2 treated groups gradually decreased serum glucose level (7.15 ±0.67 to 5.94 ± 1.19 and 7.20 ± 0.93 to 5.28 ±1.03 respectively) and reducing effect by Ext-2 was significant (p=0.001). Both extract showed lower liver glycogen level compared with GT group [5.0±2.5 Vs 17.7±6.5 (Ext-1 vs GT) and 7.5±6.4 Vs 17.7±6.5 (Ext-2 vs GT)] and even Ext-1 manifested significant effect (p=0.05). Additionally, lipid profile estimation revealed no significant improvement by the consumption of both the extracts. Conclusion: On the basis of current investigations, it may be concluded that both variety of jute’s leaf demonstrated hypoglycemic properties in Type 2 diabetic model rats; further in-depth studies are recommended to explore the exact mechanism(s) of hypoglycemic effect.

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