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The C57BL/6-Ins2Akita mouse (B6-Akita) is a model of spontaneous early-onset diabetes mellitus, characterized by a reduced number of pancreatic beta cells expressing a mutant non-functional isoform of insulin. B6-Akitas are characterized by hypoinsulinemia and hyperglycemia. We have assessed nerve function and structure to determine if Akita mice were a suitable model for the study of diabetic neuropathy. Foot sensory nerve amplitudes and motor nerve conduction velocity were significantly reduced in 6 month old diabetic Akita compared to age matched Ins2+/+ control mice (p<0.05). These results demonstrate that B6-Akita mice exhibit impaired peripheral nerve function. To determine if islet transplantation would reverse the neurological defects we examined sensory nerve morphology comparing in 7 week old B6-Akita mice which had undergone syngeneic pancreatic islet transplantation (Akita+PIT) ∼100 days prior to saphenons nerve biopsy with age matched non-islet transplanted B6-Akitas (n=3). Blood glucose levels, taken weekly were significantly reduced in Akita+PIT group. Akita+PIT mice had glucose levels <200mg/dL, 1 wk after engraftment with islets. In comparison, non-transplanted mice always exhibited blood glucose levels >500mg/dL. There was no significant difference in: Fascicular area (Akita+PIT (0.15 ± 0.04) v Akita 0.05 ± 0.01), p=0.136); myelinated nerve fibre density (no.mm-2) (Akita+PIT (20206 ± 1360) vs. Akita (21244 ± 2012), p=-0.633) or endoneurial capillary density (no.mm-2) (Akita+PIT (68.5 ± 10.2) v Akita (68.2 ± 11.0), p=l.0). However, detailed electroumicroscopy of the myelinated fibres demonstrated that islet transplantation protected against a reduction in myelinated fibre (Akita+PIT (32.2 ± 4.5) v Akita (22.3 ± 5.2) p=0.07) and axon (Akita+PIT (12.4±1.9) v Akita (7.8 ± 3.2) p=-0.07) areas (µm2); without a change in the G ratio (Akita+PIT (0.61 ± 0.06) v Akita (0.57 ± 0.04) p=0.29). In conclusion B6-Akita mice demonstrate significant reductions in nerve function and structural abnormalities include a reduction of myelinated fibre and axon area which is prevented by pancreatic islet transplantation. [ABSTRACT FROM AUTHOR]

Increased proliferation and survival of cells in small pulmonary arteries (PAs) drive pulmonary arterial hypertension (PAH). Because cell growth mediated by the mTOR-containing mTORC1 complex is inhibited by tuberous sclerosis complex 2 (TSC2), we investigated the role of this GTPase-activating protein in PAH pathology. TSC2 abundance was decreased in remodeled small PAs and PA vascular smooth muscle cells (PAVSMCs) from patients with PAH or from rodent pulmonary hypertension (PH) models, as well as PAVSMCs maintained on substrates that reproduced pathology-induced stiffness. Accordingly, mice with smooth muscle-specific reduction in TSC2 developed PH. At the molecular level, decreased TSC2 abundance led to stiffness-induced PAVSMC proliferation, increased abundance of the mechanosensitive transcriptional coactivators YAP/TAZ, and enhanced mTOR kinase activity. Moreover, extracellular matrix (ECM) produced by TSC2-deficient PAVSMCs stimulated the proliferation of nondiseased PA adventitial fibroblasts and PAVSMCs through fibronectin and its receptor, the α 5 β 1 integrin. Reconstituting TSC2 in PAVSMCs from patients with PAH through overexpression or treatment with the SIRT1 activator SRT2104 decreased YAP/TAZ abundance, mTOR activity, and ECM production, as well as inhibited proliferation and induced apoptosis. In two rodent models of PH, SRT2104 treatment restored TSC2 abundance, attenuated pulmonary vascular remodeling, and ameliorated PH. Thus, TSC2 in PAVSMCs integrates ECM composition and stiffness with pro-proliferative and survival signaling, and restoring TSC2 abundance could be an attractive therapeutic option to treat PH.

Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.