86,690 research outputs found
Prevenzione primaria della morte improvvisa nel post-infarto : le nuove Linee-Guida AHA/ACC/ESC 2006
No full textAdvanced glycation endproducts and plaque instability: A link beyond diabetes
No full text[No abstract available
Tackling myocardial oxidative stress with empagliflozin: Are we big enough to fight heart failure with preserved ejection fraction?
No full textMicroRNA profiling unveils hyperglycaemic memory in the diabetic heart
No full textAIMS Recent randomized trials suggest that intensive glycaemic control fails to reduce heart failure-related events in patients with diabetes. The molecular cues underlying persistent myocardial damage despite normoglycaemia restoration remain elusive. MicroRNAs (miRNAs), a class of small non-coding RNAs, orchestrate transcriptional programs implicated in adverse cardiac remodelling. The present study investigates whether miRNAs participate to hyperglycaemic memory in the diabetic heart. METHODS AND RESULTS miRNA landscape was assessed by Mouse miRNome miRNA PCR Arrays in left ventricular specimens collected from 4-month-old streptozotocin-induced diabetic mice, with or without intensive glycaemic control by slow-release insulin implants. A dysregulation of 316 out of 1008 total miRNAs was observed in the diabetic hearts when compared with controls. Of these, 209 were up-regulated and 107 were down-regulated by >2.0-fold. Interestingly enough, the expression of 268 of those miRNAs remained significantly altered in diabetic mice even after subsequent normoglycaemia. Ingenuity pathway analysis revealed that dysregulated miRNAs were implicated in myocardial signalling networks triggering apoptosis (miR-320b, miR-378, miR-34a), fibrosis (miR-125b, miR-150, miR-199a, miR-29b, miR30a), hypertrophic growth (miR-1, miR-150, miR-199a, miR-133a, miR-214, miR-29a, miR-125b, miR-221, miR-212), autophagy (miR-133a, miR-221, miR-212, miR30a), oxidative stress (miR-221, miR-146a, miR-34a, miR-210, miR-19b, miR-125b, miR27a, miR-155), and heart failure (miR-423, miR-499, miR-199a), respectively. CONCLUSIONS Glycaemic control is not able to rescue hyperglycaemia-induced alterations of miRNA landscape in the diabetic heart. These findings may provide novel insights to understand why diabetic cardiomyopathy progresses despite normalization of blood glucose levels
Pin1 inhibitor Juglone prevents diabetic vascular dysfunction
No full textBackground Atherosclerosis is a major cause of mortality in patients with diabetes. However, novel breakthrough therapies have yet to be approved in this setting. Prolyl-isomerase-1 (Pin1) is emerging as a key molecule implicated in vascular oxidative stress and inflammation. In the present study, we investigate whether pharmacological inhibition of Pin1 may protect against diabetes-induced oxidative stress, endothelial dysfunction and vascular inflammation. Methods and Results Experiments were performed in human aortic endothelial cells (HAECs) exposed to normal (5 mmol/L) or high glucose (25 mmol/L) concentrations, in the presence of Pin1 inhibitor Juglone (10 μM) or vehicle (< 1% ethanol). In parallel, streptozotocin-induced diabetic mice were treated with Juglone i.p. every other day for 30 days (1 mg/Kg). Organ chamber experiments were performed in aortic rings to assess endothelium-dependent relaxations to acetylcholine (Ach 10- 9 to 10- 6 mol/L). Mitochondrial oxidative stress, organelle integrity as well as NF-kB-dependent inflammatory signatures were determined both in HAECs and aortas from diabetic mice. In HAECs, ambient hyperglycemia increased mitochondrial superoxide anion generation while treatment with Juglone prevented this phenomenon. Pharmacological inhibition of Pin1 also preserved mitochondrial integrity, nitric oxide availability and endothelial expression of adhesion molecules. Interestingly enough, endothelial dysfunction, oxidative stress and NF-kB-driven inflammation were significantly attenuated in diabetic mice chronically treated with Juglone as compared to vehicle-treated animals. Conclusion Pharmacological inhibition of Pin1 by Juglone prevents hyperglycemia-induced vascular dysfunction. Taken together, our findings may set the stage for novel therapeutic approaches to prevent vascular complications in patients with diabetes
Reprogramming ageing and longevity genes restores paracrine angiogenic properties of early outgrowth cells
No full textAIMS: Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66(Shc) and the AP-1 transcription factor JunD, contribute to age-related EOCs dysfunction in humans.
METHODS AND RESULTS: Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66(Shc) gene up-regulation and reduced JunD expression. Deregulation of p66(Shc) and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 (-) generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66(Shc) silencing or JunD overexpression blunted age-related O2 (-) production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs.
CONCLUSION: Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly
SIRT1, p66Shc, and set7/9 in vascular hyperglycemic memory: Bringing all the strands together
No full text[No abstract available
Targeting chromatin remodeling to prevent cardiovascular disease in diabetes
No full textDiabetes is a major cause of cardiovascular morbidity and mortality and its prevalence is rapidly increasing worldwide. Despite clear advances in developing effective glucose-lowering drugs, clinical trials have recently shown that intensive glycemic control failed to reduce cardiovascular events in the diabetic population. These findings support the concept that the hyperglycemic environment may be remembered in the cardiovascular system. This phenomenon has been recently defined as "metabolic memory" and may contribute to explain the progression of diabetic vascular complications despite achievement of target HbA1c levels. In this regard, epigenetic changes of DNA/histone complexes are emerging as important modulators of oxidant and inflammatory genes, thus leading to persistent cardiac and vascular dysfunction. Over the last few years, the rapid development of many compounds (i.e. histone deacetylase and histone acetyltransferase inhibitors) able to erase adverse chromatin signatures led to the perception that reverting hyperglycemic damage might be possible and represents an attractive challenge. Here we critically discuss recent evidence supporting the concept that chromatin alterations are key drivers of cardiovascular disease and describe the emerging potential of chromatin modifying agents for the reprogramming of detrimental epigenetic signatures in patients with cardiometabolic disturbances
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