1,720,998 research outputs found
Delineating a miR Signature in Patients with End Stage Renal Disease to Mitigate Left Ventricular Hypertrophy
Get PDFIdentifying the differential expression of microRNAs (miRs) in end-stage renal disease (ESRD)patients may be indispensable for advancing therapeutic targets in this patient population. The
dysregulation of Fibroblast Growth Factor 23 (FGF23) and Klotho has been strongly linked to
ESRD, particularly by contributing to left ventricular hypertrophy (LVH). Nocturnal
hemodialysis (NHD) offers notable physiological benefits over conventional hemodialysis
(CHD) modalities, primarily by attenuating LVH. Therefore, it was hypothesized that the
differential expression of miRs in patients transitioning from CHD to NHD may regulate LVH
through modulating Klotho and FGF23 signaling. We identified six miRs in the serum of
patients who transitioned to NHD, with downstream targets involved in the FGF23/Klotho
signaling axis. Targeted inhibition of miR-200c-3p and FGF23 resulted in mitigation of LVH
and attenuation of fibrosis by downregulating key signaling mediators in this axis. These
findings present a novel therapeutic approach for addressing cardiac complications in ESRD
patients.M.Sc
The Association of Clonal Hematopoiesis and Adverse Outcomes in Lung and Heart Transplant Recipients
Get PDFBackground: Clonal hematopoiesis (CH), a clonal expansion of hematopoietic stem cells with specific somatic mutations, could be the potential basis for a non-invasive prognostic tool for solid organ transplant (SOT) recipients.Methods: This is a retrospective study. Genetic sequencing was performed in 101 lung and 235 heart transplant recipients. Samples were collected at the time of transplant. For heart transplant patients, an additional blood sample was collected one-year post-transplant. Clinical data was collected from the patient's electronic medical record.
Results: In lung transplant recipients, there was no association found between CH mutations and different adverse outcomes (p>0.05). In heart transplant recipients with CH, there was an increased risk of developing AMR (p=0.001), and CAV grade 2/3 (p=0.025). Those who developed CH one-year post-transplant had no association to different major adverse outcomes (p>0.05).
Conclusion: This study addresses a significant research gap in the association of CH and various post-transplant outcomes.M.Sc
The Role of Cdk1 in the Regulation of Cardiomyocyte Proliferation in the Early Postnatal and Adult Period
No full textAdult mammalian cardiomyocytes (CM) are postmitotic cells that lose their proliferate capacity shortly after birth. This is problematic specially when the heart is subjected to an insult resulting in CM loss. Thus, understanding factors that regulate CM proliferation needed for repair is of great clinical importance. There is differential expression of Cdk1 gene, a cell cycle regulator that initiates cytokinesis throughout the early post-natal period. We hypothesized that the loss of Cdk1 would result in perturbation in cell cycle progression. The loss of Cdk1 in the murine heart, results in prolonged CM proliferation with concomitant alterations in the expression of cell cycle activators and inhibitors as determined by mRNA profiling and Western blot analysis. These results provide novel data on the molecular mechanisms that govern the switch of CM from a proliferative to quiescent state.M.Sc
Control of Cardiomyocyte Proliferation by p53/MDM2-Regulated microRNAs
No full textDefining the roadblocks responsible for adult cardiomyocyte cell cycle arrest lies at the core of developing cardiac regenerative therapies. Inactivation of the p53/MDM2 tumor suppressor circuitry in the heart caused a significant increase in cardiomyocyte proliferation, through an upregulation of factors involved in cell cycle re-entry. These factors may be regulated by microRNAs (miRNAs), in quiescent cardiomyocytes. Therefore, we hypothesized that inactivation of p53/MDM2-regulated miRNAs could promote the expression of cell cycle activators and induce proliferation of cardiomyocytes. Comparison of miRNA expression profiles from cardiac specific p53/MDM2 double knockout (DKO) mouse hearts and wild type controls revealed 11 miRNAs that were downregulated in the "proliferative" DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these 11 miRNAs in neonatal rat cardiomyocytes significantly increased the occurrence of cytokinesis, revealing a novel subset of p53/MDM2-regulated miRNAs responsible for maintaining cell cycle arrest in the heart.M.Sc
Control of Cardiomyocyte Proliferation by p53/MDM2-Regulated microRNAs
Get PDFDefining the roadblocks responsible for adult cardiomyocyte cell cycle arrest lies at the core of developing cardiac regenerative therapies. Inactivation of the p53/MDM2 tumor suppressor circuitry in the heart caused a significant increase in cardiomyocyte proliferation, through an upregulation of factors involved in cell cycle re-entry. These factors may be regulated by microRNAs (miRNAs), in quiescent cardiomyocytes. Therefore, we hypothesized that inactivation of p53/MDM2-regulated miRNAs could promote the expression of cell cycle activators and induce proliferation of cardiomyocytes. Comparison of miRNA expression profiles from cardiac specific p53/MDM2 double knockout (DKO) mouse hearts and wild type controls revealed 11 miRNAs that were downregulated in the "proliferative" DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these 11 miRNAs in neonatal rat cardiomyocytes significantly increased the occurrence of cytokinesis, revealing a novel subset of p53/MDM2-regulated miRNAs responsible for maintaining cell cycle arrest in the heart.M.Sc
The Application of Dialysis and Metabolomics to Preserve Heart Function During Ex Situ Heart Perfusion
Get PDFHeart failure affects 7.5 million people globally and is the primary cause of death for over 300,000 people annually in North America. The gold standard treatment for eligible end-stage heart failure patients is heart transplantation. However, even with extended donation criteria, there is a mismatch between the number of donors and recipients. Beyond the use of donation after brain death (DBD) organs, hearts obtained from donation after circulatory death (DCD) donors have been proposed as an alternative to expand the donor pool. Ex situ heart perfusion (ESHP) has been developed as a platform to revive hearts outside the body and can be used to evaluate heart function after DCD, prior to transplantation. Unfortunately, heart function declines during prolonged ESHP secondary to edema and altered metabolism. Therefore, we hypothesize that defining the changes in the metabolome during ESHP and the use of hemodialysis may improve heart function during prolonged ESHP. We have demonstrated the use of hemodialysis during ESHP significantly improves left ventricular and coronary vasomotor function. Furthermore, we have shown that carnitine synthesis is significantly impaired in both working mode and nonworking mode ESHP hearts.M.Sc
The Role of microRNAs in the Regulation of Cardiomyocyte Proliferation in the Early Postnatal Period
Get PDFThe regenerative capacity of the mammalian heart is lost quickly after birth when CM stop dividing and undergo cell cycle arrest. CM were shown to only proliferate in the first 12 hours following birth, with proliferative arrest occurring at 1d. A differential expression of cell cycle genes was found during this time. Cell cycle genes have been shown to be regulated by microRNAs (miRNAs). Therefore, we hypothesized that a differential expression of miRNAs exists in the first hours after birth and manipulation of these miRNAs will provide the potential to promote cardiomyocyte (CM) proliferation. Profiling of miRNAs from wild type murine hearts revealed a differential expression of miRNAs that were enriched for cell cycle gene targets. The use of antagomirs was effective in significantly increasing the degree of proliferation in neonatal rat CM cytokinesis, suggesting a role for these miRNAs in the control of CM cell cycle arrest.M.Sc.2021-11-19 00:00:0
Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model
Get PDFBackground: Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in heart transplantation. Bone marrow–mesenchymal stromal cell (BM-MSC) treatment is a potentially effective cell therapy for cardiac disease. We investigated the effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a heterotopic heart transplantation (HHT) model associated with I/R injury. Methods: Hearts of wild-type Lewis (WT LEW) rats were harvested and transplanted heterotopically into the necks of recipient WT LEW rats. Forty-eight hours after HHT, BM-MSCs were injected intravenously into animals in the experimental group, whereas controls received normal saline (NS). Results: Eight days after BM-MSC injection, fractional shortening of transplanted hearts was significantly higher and left ventricular systolic diameter was lower in the BM-MSC group compared with controls, whereas no differences were found 28 days after infusion. A reduction in ventricular remodeling and cardiac fibrosis was observed by histochemical analysis and confirmed by cardiac magnetic resonance imaging in the BM-MSC group. The perivascular stromal cells’ density and the number of capillaries were increased whereas the number of apoptotic cells decreased significantly in transplanted hearts in the BM-MSC group compared with the NS group. Conclusions: We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neo-vascularization and decreased cardiomyocyte apoptosis of the transplanted heart in a heterotopic transplantation model after intravenous infusion of BM-derived MSCs. Our data suggest that clinical studies with BM-MSCs are warranted to understand their effects on cardiac graft and transplant recipient survival.Fil: Montanari, Sonia. University Health Network; Canadá. University of Toronto; CanadáFil: Dayan, Victor. University Health Network; CanadáFil: Yannarelli, Gustavo Gabriel. University Health Network; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Billia, Filio. Toronto General Hospital; CanadáFil: Viswanathan, Sowmya. University Health Network; CanadáFil: Connelly, Kim A.. Keenan Research Centre; CanadáFil: Keating, Armand. University Health Network; Canadá. University of Toronto; Canad
Analysis of differential gene expression in a complex differentiating hierarchy by global amplification of cDNA from single hemopoietic precursors
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University of TorontoUnderlying the process of hemopoietic differentiation is the activation and suppression of distinct genes. To understand the molecular mechanisms that control these events, global amplification of polyadenylated mRNAs was applied to single hemopoietic precursor cells. Siblings from nascent colony starts were useful indicators of the differentiative potential of hemopoietic precursor cells consumed in the global PCR reaction. Siblings exhibited uniform outcomes, although differentiative outcomes varied from one clone to another. By combining global PCR with sibling analysis, a set of cDNA samples was generated from 16 distinct stages of hemopoietic development. It was then possible to map the mRNA expression of 29 genes known to be involved in hemopoietic differentiation, growth and apoptosis, in hemopoietic precursors with differing commitment and maturation states. These results provided novel information on stage- and lineage-specific expression of these genes. A PCR-based subtractive hybridization approach was used to identify novel genes in single hemopoietic precursors. By hybridizing the subtractive clones to the set of cDNA samples, those with stage- and lineage-specific patterns of expression were identified. To establish whether the actions of growth factors on hemopoietic precursor cells were mediated directly or via accessory cells, the expression of 19 distinct hemopoietic growth factor receptor (HGFR) subunits were mapped using an extended set of amplified cDNA samples, representing 21 distinct stages of hemopoietic development. Southern analysis of the set of cDNA samples lacked the sensitivity required. Therefore, a secondary PCR was done targeting each HGFR subunit individually. It was observed that most HGFRs were broadly expressed throughout the hemopoietic hierarchy and that individual hemopoietic precursors expressed transcripts for more than one HGFR. This work establishes the potential for mapping the expression of any gene, of any abundance, to a level of resolution unobtainable before, and identifying novel genes that may be involved in hemopoietic commitment and differentiation.Ph.D
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