Search Results (5)

Background: Obese and pre-diabetic women have a higher risk for cardiovascular death than age-matched men with the same symptoms, and there are no effective treatments. We reported that obese and pre-diabetic female Zucker Diabetic Fatty (ZDF-F) rats recapitulate metabolic and cardiac pathology of young obese and pre-diabetic women and exhibit suppression of cardio-reparative AT2R. Here, we investigated whether NP-6A4, a new AT2R agonist with the FDA designation for pediatric cardiomyopathy, mitigate heart disease in ZDF-F rats by restoring AT2R expression. Methods: ZDF-F rats on a high-fat diet (to induce hyperglycemia) were treated with saline, NP-6A4 (10 mg/kg/day), or NP-6A4 + PD123319 (AT2R-specific antagonist, 5 mg/kg/day) for 4 weeks (n = 21). Cardiac functions, structure, and signaling were assessed by echocardiography, histology, immunohistochemistry, immunoblotting, and cardiac proteome analysis. Results: NP-6A4 treatment attenuated cardiac dysfunction, microvascular damage (−625%) and cardiomyocyte hypertrophy (−263%), and increased capillary density (200%) and AT2R expression (240%) (p < 0.05). NP-6A4 activated a new 8-protein autophagy network and increased autophagy marker LC3-II but suppressed autophagy receptor p62 and autophagy inhibitor Rubicon. Co-treatment with AT2R antagonist PD123319 suppressed NP-6A4’s protective effects, confirming that NP-6A4 acts through AT2R. NP-6A4-AT2R-induced cardioprotection was independent of changes in body weight, hyperglycemia, hyperinsulinemia, or blood pressure. Conclusions: Cardiac autophagy impairment underlies heart disease induced by obesity and pre-diabetes, and there are no drugs to re-activate autophagy. We propose that NP-6A4 can be an effective drug to reactivate cardiac autophagy and treat obesity- and pre-diabetes-induced heart disease, particularly for young and obese women. Full article

Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described marked ultrastructural (US) remodeling of the neurovascular unit (NVU) in type 2 diabetic db/db female mice. Herein, we tested whether the SGLT-2 inhibitor, empagliflozin (EMPA), protects the NVU from abnormal remodeling in cortical gray and subcortical white matter. Ten-week-old female wild-type and db/db mice were divided into lean controls (CKC, n = 3), untreated db/db (DBC, n = 3), and EMPA-treated db/db (DBE, n = 3). Empagliflozin was added to mouse chow to deliver 10 mg kg⁻¹ day⁻¹ and fed for ten weeks, initiated at 10 weeks of age. Brains from 20-week-old mice were immediately immersion fixed for transmission electron microscopic study. Compared to CKC, DBC exhibited US abnormalities characterized by mural endothelial cell tight and adherens junction attenuation and/or loss, pericyte attenuation and/or loss, basement membrane thickening, glia astrocyte activation with detachment and retraction from mural cells, microglia cell activation with aberrant mitochondria, and oligodendrocyte–myelin splitting, disarray, and axonal collapse. We conclude that these abnormalities in the NVU were prevented in DBE. Empagliflozin may provide neuroprotection in the diabetic brain. Full article

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. In this study, we tested the hypothesis that neurovascular unit(s) (NVU), oligodendrocytes, and myelin within cerebral cortical grey matter and deeper transitional zone regions between the cortical grey matter and white matter may be abnormal. The monogenic (Lepr^db) female diabetic db/db [BKS.CgDock7^m +/+ Lepr^db/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks of age), left-brain hemispheres of the DBC and age-matched non-diabetic wild type control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We found prominent remodeling of oligodendrocytes with increased nuclear chromatin condensation and volume and increased numbers of active myelination sites of the cytoplasm in transition zones. Marked dysmyelination with outer myelin lamellae sheath splitting, separation, and ballooning with aberrant mitochondria in grey matter and similar myelin remodeling changes with marked disarray with additional axonal collapse in transitional zones in DBC as compared to CKC models. Full article

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular remodeling. The monogenic (Lepr^db) female diabetic db/db [BKS.CgDock7^m +/+Lepr^db/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks), left-brain hemispheres of the DBC and age-matched nondiabetic control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We observed an attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickened basement membranes, adherent red and white blood cells, neurovascular unit microbleeds and pathologic remodeling of protoplasmic astrocytes. In this second of a three-part series, we focus on the observational ultrastructural remodeling of microglia and mitochondria in relation to the NVU in leptin receptor deficient DBC models. This study identified novel ultrastructural core signature remodeling changes, which consisted of invasive activated microglia, microglial aberrant mitochondria with nuclear chromatin condensation and adhesion of white blood cells to an activated endothelium of the NVU. In conclusion, the results implicate activated microglia in NVU uncoupling and the resulting ischemic neuronal and synaptic damage, which may be related to impaired cognition and diabetic cognopathy. Full article

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with cognitive impairment, known as diabetic cognopathy. In this study, we tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions display abnormal cellular remodeling. The monogenic (Lepr^db) female diabetic db/db (BKS.CgDock7^m +/+Lepr^db/J; DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (at 20 weeks of age), left-brain hemispheres of the DBC and age-matched non-diabetic wild-type control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We found attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickening of the basement membrane, aberrant mitochondria, and pathological remodeling of protoplasmic astrocytes. Additionally, there were adherent red blood cells and NVU microbleeds (cortical layer III) in DBC mice, which were not observed in CKC animals. While this study represents only a “snapshot in time”, it does allow for cellular remodeling comparisons between DBC and CKC. In this paper, the first of a three-part series, we report the observational ultrastructural remodeling changes of the NVU and its protoplasmic astrocytes in relation to the surrounding neuropil. Having identified multiple abnormal cellular remodeling changes in the DBC as compared to CKC models, we will design future experiments to evaluate various treatment modalities in DBC mice. Full article