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Circulation research [journal]
- MicroRNA Induced Cardiac Reprogramming In Vivo: Evidence for Mature Cardiac Myocytes and Improved Cardiac Function. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 28.
Rationale: A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a specific combination of micro-RNAs (miR combo) into the infarcted myocardium leads to direct in vivo reprogramming of non-cardiac myocytes to cardiac myocytes. However, the biologic and functional consequences of such reprogramming are not yet known. Objective: The aim of this study was to determine whether non-cardiac myocytes directly reprogrammed using miRNAs in vivo develop into mature functional cardiac myocytes in situ, and whether reprogramming leads to improvement of cardiac function. Methods and Results: We subjected FSP1-Cre mice/tdTomato mice to cardiac injury by permanent ligation of the left anterior descending coronary artery (LAD) and injected lentiviruses encoding miR combo or a control nontargeting miRNA. miR combo significantly increased the number of reprogramming events in vivo. Five-to-six weeks following injury, morphological and physiological properties of tdTomato(-) and tdTomato(+) cardiac myocyte-like cells were analyzed ex vivo. tdTomato(+) cells expressed cardiac myocyte markers, sarcomeric organization, excitation-contraction coupling, and action potentials characteristic of mature ventricular cardiac myocytes (tdTomato(-) cells). Reprogramming was associated with improvement of cardiac function, as analyzed by serial echocardiography. There was a time delayed and progressive improvement in fractional shortening and other measures of ventricular function, indicating that miR combo promotes functional recovery of damaged myocardium. Conclusions: The findings from this study further validate the potential utility of miRNA-mediated reprogramming as a therapeutic approach to promote cardiac regeneration following myocardial injury.
- Relationships Between Fine Particulate Air Pollution, Cardiometabolic Disorders and Cardiovascular Mortality. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 27.
Rationale: Growing evidence suggests that long-term exposure to fine particulate matter (PM2.5) air pollution contributes to risk of cardiovascular disease (CVD) morbidity and mortality. There is uncertainty regarding who are most susceptible. Individuals with underlying cardiometabolic disorders, including hypertension, diabetes, and obesity, may be at greater risk. PM2.5 pollution may also contribute to cardiometabolic disorders, augmenting CVD risk. Objective: This analysis evaluates relationships between long-term PM2.5 exposure and cardiometabolic disease on risk of death from CVD and cardiometabolic conditions. Methods and Results: Data on 669,046 participants from the American Cancer Society, Cancer Prevention Study II cohort were linked to modeled PM2.5 concentrations at geocoded home addresses. Cox proportional hazards regression models were used to estimate adjusted hazards ratios (HR) for death from CVD and cardiometabolic diseases based on death-certificate information. Effect modification by pre-existing cardiometabolic risk factors on the PM2.5-CVD mortality association was examined. PM2.5 exposure was associated with CVD mortality, with the HR (95% CI) per 10 µg/m(3) increase in PM2.5 equal to 1.12 (1.10-1.15). Deaths linked to hypertension and/or diabetes (mentioned on death certificate as either primary or contributing cause of death) were also associated with PM2.5. There was no consistent evidence of effect modification by cardiometabolic disease risk factors on the PM2.5-CVD mortality association. Conclusions: Pollution-induced CVD mortality risk is observed for those with and without existing cardiometabolic disorders. Long-term exposure may also contribute to the development or exacerbation of cardiometabolic disorders, increasing risk of CVD and cardiometabolic disease mortality.
- Genetic Deletion of Rnd3/RhoE Results in Mouse Heart Calcium Leakage Through Upregulation of Protein Kinase A Signaling. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 27.
Rationale: Rnd3, a small Rho GTPase, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation. The biological function of Rnd3 in the heart remains unexplored. Objective: To define the functional role of the Rnd3 gene in the animal heart and investigate the associated molecular mechanism. Methods and Results: By loss-of-function approaches, we discovered that Rnd3 is involved in calcium regulation in cardiomyocytes. Rnd3-null mice died at the embryonic stage with fetal arrhythmias. The deletion of Rnd3 resulted in severe Ca(2)+ leakage through destabilized ryanodine receptor type 2 (RyR2) Ca(2+) release channels. We further found that downregulation of Rnd3 attenuated β2-adrenergic receptor (β2AR) lysosomal targeting and ubiquitination, which in turn resulted in the elevation of β2AR protein levels leading to the hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized RyR2 channels. This irregular spontaneous Ca(2+) release can be curtailed by PKA inhibitor treatment. Increases in the PKA activity along with elevated cyclic adenosine monophosphate (cAMP) levels were detected in Rnd3-null embryos, in neonatal rat cardiomyocytes, and non-cardiac cell lines with Rnd3 knockdown, suggesting a general mechanism for Rnd3-mediated PKA signaling activation. β2AR blocker treatment reduced arrhythmia and improved cardiac function. Conclusions: Rnd3 is a novel factor involved in intracellular Ca(2+) homeostasis regulation in the heart. Deficiency of the protein induces RyR2 dysfunction by a mechanism that attenuates Rnd3-mediated β2AR ubiquitination, which leads to the activation of PKA signaling. Increased PKA signaling in turn promotes RyR2 hyperphosphorylation, which contributes to arrhythmogenesis and heart failure.
- Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis: Promotion of Macrophage Apoptosis and Plaque Necrosis Through IL-23 Signaling. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 27.
Rationale: Granulocyte macrophage colony stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression-the process that gives rise to clinically dangerous plaques-is unknown. Objective: To understand the role of GM-CSF in advanced atherosclerotic plaque progression. Methods and Results: Ldlr(-/-) mice and Csf2(-/-)Ldlr(-/-) mice were fed a Western-type diet for 12 wks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in two key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of IL-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell-survival protein Bcl-2 and by increasing oxidative stress. Conclusions: In LDL-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its IL-23-inducing activity rather than its role as a growth factor.
- Identification of Therapeutic Covariant microRNA Clusters in Hypoxia Treated Cardiac Progenitor Cell Exosomes using Systems Biology. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 24.
Rationale: Myocardial infarction (MI) is a leading cause of death in developed nations, and there remains a need for cardiac therapeutic systems that mitigate tissue damage and. Cardiac progenitor cells (CPCs) and other stem cell types are attractive candidates for treatment of MI; however, the benefit of these cells may be due to paracrine effects. Objective: We tested the hypothesis that CPCs secrete pro-regenerative exosomes in response to hypoxic conditions. Methods and Results: The angiogenic and anti-fibrotic potential of secreted exosomes on cardiac endothelial cells and cardiac fibroblasts were assessed. We found that CPC exosomes secreted in response to hypoxia enhanced tube formation of endothelial cells and decreased pro-fibrotic gene expression in TGF-β stimulated fibroblasts, indicating that these exosomes possess therapeutic potential. Microarray analysis of exosomes secreted by hypoxic CPCs identified eleven miRNAs that were upregulated compared to exosomes secreted by CPCs grown under normoxic conditions. Principle component analysis was performed to identify miRNAs that were co-regulated in response to distinct exosome generating conditions. To investigate the cue-signal-response relationships of these miRNA clusters with a physiological outcome of tube formation or fibrotic gene expression, partial least squares regression analysis was applied. The importance of each up- or downregulated miRNA on physiological outcomes was determined. Finally, to validate the model we delivered exosomes following ischemia-reperfusion injury. Exosomes from hypoxic CPCs improved cardiac function and reduced fibrosis. Conclusions: These data provide a foundation for subsequent research of the use of exosomal miRNA and systems biology as therapeutic strategies for the damaged heart.
- Response to letter regarding article, "embryonic stem cell-derived cardiac myocytes are not ready for human trials". [Letter]
- Circ Res 2014 Oct 24; 115(10):e30-1.
- Letter by murry et Al regarding article, "embryonic stem cell-derived cardiac myocytes are not ready for human trials". [Letter]
- Circ Res 2014 Oct 24; 115(10):e28-9.
- Oxygen: double-edged sword in cardiac function and repair. [Journal Article]
- Circ Res 2014 Oct 24; 115(10):824-5.
- Copy number variants and the genetic enigma of congenital heart disease. [Editorial]
- Circ Res 2014 Oct 24; 115(10):821-3.
- Hypoxia in plaque macrophages: a new danger signal for interleukin-1β activation? [Editorial]
- Circ Res 2014 Oct 24; 115(10):817-20.