131 research outputs found
Is it the time of seno-therapeutics application in cardiovascular pathological conditions related to ageing?
No full textIt rates that in 2030, the cardiovascular diseases (CVD) will result in 40% of all deaths and rank as the leading
cause. Thus, the research of appropriate therapies able to delay or retard their onset and progression is growing.
Of particular interest is a new branch of the medical science, called anti-ageing medicine since CVD are the result of
cardiovascular ageing. Senescent cells (SC) accumulate in cardiovascular system contributing to the onset of
typical age-related cardiovascular conditions (i.e., atherosclerosis, medial aorta degeneration, vascular remodeling,
stiffness). Such conditions progress in cardiovascular pathologies (i.e., heart failure, coronary artery disease,
myocardial infarction, and aneurysms) by evocating the production of a proinflammatory and profibrotic
senescence-associated secretory phenotype (SASP). Consequently, therapies able to specifically eliminate SC are
in developing. The senotherapeutics represents an emerging anti-SC treatment, and comprises three therapeutic
approaches: (a) molecules to selectively kill SC, defined senolytics; (b) compounds able in reducing evocated SC
SASP, acting hence as SASP suppressors, or capable to change the senescent phenotype, called senomorphics; (c)
inhibition of increase of the number of SC in the tissues. Here, it describes them and the emerging data about
current investigations on their potential clinical application in CVD, stressing benefits and limitations, and suggesting
potential solutions for applying them in near future as effective anti-CVD treatment
Induced Pluripotent Stem Cells for Cardiac Regeneration
No full textInduced pluripotent stem (iPS) cells are a type of pluripotent stem cell artificially derived from a non-pluripotent cell—typically an adult somatic cell—by inducing a “forced” expression of specific genes. Typically, iPS cells are generated by retroviral induction of transcription factors, OCT (octamer-binding transcription factor)-4, SRY (sex determining region Y)-box 2 also known as SOX2, kruppel-like factor (KLF)-4, and c-MYC, in fibroblasts. The development of iPS cells could be a strategy to overcome the limitations of human embryonic stem cells. iPS cells can replace animal and ES experiments in drug development and toxicity tests and for testing mechanicistic hypotheses of diseases. Although the creation of multiple lineages with iPS cells can seem limitless, a number of challenges need to be addressed in order to effectively use these cell lines for disease modeling. These include the low efficiency of iPS cell generation without genetic alterations, the possibility of tumor formation in vivo, the random integration of retroviral-based delivery vectors into the genome, and unregulated growth of the remaining cells that are partially reprogrammed and refractory to differentiation. The establishment of protein or RNA-based reprogramming strategies will help generate human iPS cells without permanent genetic alterations for future development of personalized medicine
Prevention and Clinical Management of Cardiovascular Damage Induced by Anticancer Drugs: Need gor Early Biomarkers snd Cardio- snd Vasculo-Protection in Personalized Therapy
No full textThe use of chemotherapy has largely improved the prognosis of cancer patients in the past two decades. However, the advent of more effective anticancer therapies has led to a higher incidence of cardiovascular toxicity that shows an increased incidence and represents a significant determinant of quality of life and mortality during ongoing treatment and in long-term survivors of cancer. In this setting, the primary objective for cardiologists and oncologists is the early identification of patients at high risk for developing cardiovascular toxicity and the identification of the cardiovascular cardiotoxicity in the earliest stages to personalize cancer therapy, arrange preventive interventions, and implement cardioprotective treatment.
Recently, there is growing interest on the “omics” technologies, including genomics, transcriptomics, proteomics, and metabolomics, which allow the description of a large number of molecular features and have the potential to identify new factors that contribute to cardiac and endothelial function and how they interact. These technologies could play a pivotal role in unraveling the pathophysiology of vascular damage induced by anticancer treatment, in predicting the cardiovascular damage, and in monitoring individual responses to antineoplastic drugs. Leveraging multi-omics may better individuate the highly sensitive biomarkers of developing cardiovascular toxicity and further the goal of precision medicine
New aspects of p66Shc in ischaemia reperfusion injury and other cardiovascular diseases
No full textAlthough reactive oxygen species (ROS) act as crucial factors in the onset and progression of a wide array of diseases, they are also involved in numerous signal pathways related to cell metabolism, growth and survival. ROS are produced at various cellular sites and a general consensus exists that mitochondria generate the largest amount, especially in cardiomyocytes. However, the identification of the most relevant sites within mitochondria, the interaction among the various sources, and the events responsible for the increase in ROS formation under pathological conditions remain issues that are highly debated, but far from convincing conclusions. Here, we review information linking the adaptor protein p66Shc with cardiac injury induced by ischemia and reperfusion (I/R), including the contribution of risk factors, such as metabolic syndrome and aging. In response to several stimuli, p66Shc migrates into mitochondria where it catalyzes electron transfer from cytochrome c to oxygen resulting in hydrogen peroxide formation. Deletion of p66Shc has been shown to reduce I/R injury as well as vascular abnormalities related to diabetes and aging. On the other hand, p66Shc-induced ROS formation is involved in insulin signaling and might contribute to self-endogenous defenses against mild I/R injury. Besides physiological and pathological aspects, for the first time available information is reviewed on compounds or conditions modulating p66Shc expression and activity
Diagnostic and prognostic relevance of red blood cell distribution width for vascular aging and cardiovascular diseases
No full textEvidence suggests association of red blood cell distribution width (RDW) with cardiovascular diseases (CVDs). On the contrary, we underline that the sole RDW values cannot represent a valid CVD biomarker. High RDW values are expression of biological effects of a lot of both endogenous and exogenous factors (i.e. age, sex, genetic background, inflammation, hormones, drugs, diet, exercise, haematological analyzers, and ranges of values), modulating the biology and physiology of erythrocytes. Thus, the singular monitoring of RDW cannot be used to predict cardiovascular disorders. Accordingly, we have reviewed the evidence for potential relationship of RDW values with alterations in the cardiovascular system (i.e. regenerative capacity, endothelial turnover and senescence of cardiovascular cells), associated with vascular ageing and disease. In addition, we also highlight the inevitable impact of biases in clinical application of RDW related to CVDs. Based on our revision of literature, we suggest a combined evaluation of RDW with other emerging biomarkers related to vascular aging and the diagnosis and prognosis of CVDs, including telomere length of leukocytes, circulating nucleated red blood cells (nRBC) and endothelial progenitor cells (EPCs). Promising data deriving from additional future studies could permit both to propose them as a multibiomarker profile and create an appropriate algorithm, which can facilitate the diagnosis and to predict the prognosis of different CVDs based on vascular aging
Proteomic analysis of the secretome of adipose tissue-derived murine mesenchymal cells overexpressing telomerase and myocardin
No full textUnderstanding mechanisms of the therapeutic effects of stem/progenitor cells, among which adipose tissue-derived mesenchymal stromal cells (AT-MSCs), has important implications for clinical use. Since the majority of such cells die within days or weeks after transplantation and do not persist in the transplanted organ or tissue, their effects appear to be largely mediated by paracrine signaling pathways, and are enhanced by overexpression of the antisenescent protein telomerase reverse transcriptase (TERT), and the anti-apoptotic transcription factor myocardin (MYOCD).By a proteomic approach combining two-dimensional gel electrophoresis (2DE) with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF/TOF) mass spectrometry, we aimed at analyzing how soluble and vesicular secretomes of aged murine AT-MSCs and their angiogenic function are modulated by the overexpression of TERT and MYOCD.We cultured murine mock-transduced AT-MSCs and "rejuvenated" AT-MSCs overexpressing TERT and MYOCD (rTMAT-MSCs) harvested from 1-year-old male C57BL/6 mice. We established proteomes from 3 mock-transduced AT-MSCs and rTMAT-MSCs cultures in serum-free conditions, as well as their corresponding conditioned medium (CM) and exosome-enriched fractions (Exo+).Proteomic analysis revealed a 2-fold increase of matrix metalloproteinase-2 (MMP-2) and its inhibitor metalloproteinase inhibitor 2 (TIMP2) in the CM - but not in the Exo + - of rTMAT-MSCs as compared to mock-transduced AT-MSCs. At the functional level, rTMAT-MSCs-CM, and - to a lesser extent - its Exo + fraction, increased tube formation of human vein endothelial cells (HUVECs), which could be blocked by anti-MMP2 and enhanced by anti-TIMP2 antibodies, respectively. Altogether, our results identify MMP2 and its inhibitor TIMP2 as novel candidates by which rTMAT-MSCs can support angiogenesis. Our strategy also illustrates the usefulness of comparative targeted proteomic approach to decipher molecular pathways underlying rTMAT-MSCs properties
The role of mitochondrial reactive oxygen species, NO and H2S in ischaemia/reperfusion injury and cardioprotection
No full textRedox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed at decreasing mitochondrial ROS accumulation have been developed and have shown cardioprotective effects in experimental settings. However, ROS, NO and H2S play also a role in endogenous cardioprotection, as in the case of ischaemic pre‐conditioning, so that preventing their increase might hamper self‐defence mechanisms. The aim of the present review was to provide a critical analysis of formation and role of reactive species, NO and H2S in mitochondria, with a special emphasis on mechanisms of injury and protection that determine the fate of hearts subjected to I/R. The elucidation of the signalling pathways of ROS, NO and H2S is likely to reveal novel molecular targets for cardioprotection that could be modulated by pharmacological agents to prevent I/R injury
Epigenetic modulation of vascular diseases: Assessing the evidence and exploring the opportunities
No full textVascular adaptations to either physiological or pathophysiological conditions commonly require gene expression modifications in the most represented cellular elements of the vessel wall, i.e. endothelial and smooth muscle cells. In addition to transcription factors, a number of mechanisms contribute to the regulation of gene expression in these cells including noncoding RNAs, histone and DNA modifications, collectively indicated as epigenetic modifications. Here, we summarize the state of art regarding the role of epigenetic changes in major vascular diseases, and discuss the potential diagnostic and therapeutic applications of epigenetic modulation in this context
High glucose-induced hyperosmolarity impacts proliferation, cytoskeleton remodeling and migration of human induced pluripotent stem cells via aquaporin-1
No full textAbstractBackground and objective: Hyperglycemia leads to adaptive cell responses in part due to hyperosmolarity. In endothelial and epithelial cells, hyperosmolarity induces aquaporin-1 (AQP1) which plays a role in cytoskeletal remodeling, cell proliferation and migration. Whether such impairments also occur in human induced pluripotent stem cells (iPS) is not known. We therefore investigated whether high glucose-induced hyperosmolarity impacts proliferation, migration, expression of pluripotency markers and actin skeleton remodeling in iPS cells in an AQP1-dependent manner. Methods and results: Human iPS cells were generated from skin fibroblasts by lentiviral transduction of four reprogramming factors (Oct4, Sox2, Klf4, c-Myc). After reprogramming, iPS cells were characterized by their adaptive responses to high glucose-induced hyperosmolarity by incubation with 5.5mmol/L glucose, high glucose (HG) at 30.5mM, or with the hyperosmolar control mannitol (HM). Exposure to either HG or HM increased the expression of AQP1. AQP1 co-immunoprecipitated with β-catenin. HG and HM induced the expression of β-catenin. Under these conditions, iPS cells showed increased ratios of F-actin to G-actin and formed increased tubing networks. Inhibition of AQP1 with small interfering RNA (siRNA) reverted the inducing effects of HG and HM. Conclusions: High glucose enhances human iPS cell proliferation and cytoskeletal remodeling due to hyperosmolarity-induced upregulation of AQP1
Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction
No full textRATIONALE: Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. OBJECTIVES: We examined whether poly(lactic-co-glycolic acid) (PLGA) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analyzed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). METHODS: We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve month-old C57 mice underwent coronary artery ligation (Lig) to induce AMI, and were randomized into 5 treatment groups: AMI control (saline 20 microL, n=7), AMI followed by intramyocardial injection with AT-MSCs (2.5x105 cells/20 microL, n=5), or concentrated medium from AT-MSCs (CM, 20 microL, n=8), or AT-MSCs (2.5x105 cells/20 microL) conjugated with empty PAMs (n=7), or VEGF-releasing PAMs (n=8). Sham-operated mice (n=7) were used as controls. RESULTS: VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. CONCLUSIONS: AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications
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