Cardioprotective effects of sodium glucose cotransporter 2 inhibition in angiotensin II-dependent hypertension are mediated by the local reduction of sympathetic activity and inflammation

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels

Selective Bispecific T Cell Recruiting Antibody and Antitumor Activity of Adoptive T Cell Transfer

Background: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. Methods: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40+ and EpCAM+). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met+ human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. Results: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase+ melanoma cells by TCR-, as well as of CEA+ colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. Conclusions: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of AC

Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer

Background: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy.Methods: SV40 T antigen–specific T cells from T cell receptor (TCR)-I–transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR–anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40+ and EpCAM+). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met+ human tumor cell lines. Differences between experimental conditions were analyzed using the Student’s t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided.Results: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR–transduced T cells to immobilized c-Met and recognition of tyrosinase+ melanoma cells by TCR-, as well as of CEA+ colon cancer cells by chimeric antigen receptor (CAR)–modified T cells.Conclusions: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT

Modulation Of Cardiac Contractility By Antagonism Of Pleckstrin-homology Domain And Akt-1 Silencing

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Angiotensin type-2 (AT-2)-receptor activation reduces renal fibrosis in cyclosporine nephropathy: evidence for blood pressure independent effect

Synopsis Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague-Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (P &lt; 0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P &lt; 0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (P &lt; 0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases

Carbon monoxide cardiotoxicity

Cardiac dysfunction including arrhythmias and myocardial ischemia have often been reported in carbon monoxide poisoning; scattered punctiform hemorrhages throughout the heart have been documented in autopsy samples. An appropriate diagnostic approach is crucial to assess carbon monoxide cardiac damage. This evaluation may be confounded by several factors, including the absence of overt symptoms and of specific ischemic changes in the electrocardiogram. In experimental studies, laboratory animals can develop cardiac changes similar to those seen in humans and therefore proved to be useful models to study the effects and the mechanisms of cardiac damage due to carbon monoxide. These investigations, as well as others performed in vitro, provide support for a direct action of carbon monoxide on the heart, in addition to systemic hypoxia produced by carboxyhemoglobin formation. This review focuses on the diagnostic aspects of carbon monoxide cardiotoxicity. Experimental results obtained in animals and in vitro models are also discussed

Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 &micro;g/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure

Sodium Glucose Cotransporter-2 Inhibitors in Non-Diabetic Kidney Disease: Evidence in Experimental Models

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents widely used for the treatment of type 2 diabetes mellitus. A number of clinical trials in type 2 diabetic patients with different degrees of renal impairment have clearly demonstrated that SGLT2 inhibitors reduce the progression rate of diabetic kidney disease. Furthermore, recent studies have shown that SGLT2 inhibitors also exert a protective effect in the case of non-diabetic kidney disease. Consequently, it has been hypothesized that the nephroprotective activity of these drugs could exceed the canonical impact on glycemic control and that the resulting beneficial effects could be the consequence of their pleiotropic properties (proven reduction of inflammation, fibrosis, oxidative stress and sympathetic nervous activity) both at systemic and tissue levels, suggesting that the efficacy of these drugs could also be extended to non-diabetic nephropathies. This review focuses on the nephroprotective effects of SGLT2 inhibitors in different experimental models of non-diabetic kidney disease. The different glucose-independent mechanisms potentially implemented by SGLT2 inhibitors to ultimately protect the non-diabetic kidney are described in detail, and conflicting results, when present, are discussed