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1.
PLoS One ; 15(1): e0227780, 2020.
Article in English | MEDLINE | ID: mdl-31945113

ABSTRACT

The engraftment of human stem cell-derived cardiomyocytes (hSC-CMs) is a promising treatment for remuscularizing the heart wall post-infarction, but it is plagued by low survival of transplanted cells. We hypothesize that this low survival rate is due to continued ischemia within the infarct, and that increasing the vascularization of the scar will ameliorate the ischemia and improve hSC-CM survival and engraftment. An adenovirus expressing the vascular growth factor Sonic Hedgehog (Shh) was injected into the infarcted myocardium of rats immediately after ischemia/reperfusion, four days prior to hSC-CM injection. By two weeks post-cell injection, Shh treatment had successfully increased capillary density outside the scar, but not within the scar. In addition, there was no change in vessel size or percent vascular volume when compared to cell injection alone. Micro-computed tomography revealed that Shh failed to increase the number and size of larger vessels. It also had no effect on graft size or heart function when compared to cell engraftment alone. Our data suggests that, when combined with the engraftment of hSC-CMs, expression of Shh within the infarct scar and surrounding myocardium is unable to increase vascularization of the infarct scar, and it does not improve survival or function of hSC-CM grafts.


Subject(s)
Hedgehog Proteins/metabolism , Human Embryonic Stem Cells/metabolism , Myocardial Infarction/therapy , Myocytes, Cardiac/transplantation , Adenoviridae/genetics , Animals , Cell Differentiation , Coronary Vessels/diagnostic imaging , Disease Models, Animal , Genetic Vectors/genetics , Heart/diagnostic imaging , Hedgehog Proteins/genetics , Humans , Male , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/etiology , Myocardial Infarction/mortality , Myocardium/cytology , Myocytes, Cardiac/metabolism , Neovascularization, Physiologic , Rats , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Reperfusion Injury/complications , Survival Rate , Transfection , Treatment Outcome , Up-Regulation , X-Ray Microtomography
2.
PLoS One ; 9(10): e108505, 2014.
Article in English | MEDLINE | ID: mdl-25290689

ABSTRACT

Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.


Subject(s)
Gene Expression , Hepatic Stellate Cells/metabolism , Liver Diseases/genetics , RGS Proteins/genetics , Animals , Cell Line , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Endothelin-1/metabolism , Gene Expression Regulation , Hematopoietic Stem Cells/metabolism , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Liver Diseases/metabolism , Liver Diseases/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Mice, Knockout , Mice, Transgenic , RNA, Small Interfering/genetics , Signal Transduction
3.
Am J Physiol Cell Physiol ; 301(2): C478-89, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21593453

ABSTRACT

Regulator of G protein signaling (RGS) proteins, and notably members of the RGS-R4 subfamily, control vasocontractility by accelerating the inactivation of Gα-dependent signaling. RGS5 is the most highly and differently expressed RGS-R4 subfamily member in arterial smooth muscle. Expression of RGS5 first appears in pericytes during development of the afferent vascular tree, suggesting that RGS5 is a good candidate for a regulator of arterial contractility and, perhaps, for determining the mass of the smooth muscle coats required to regulate blood flow in the branches of the arterial tree. Consistent with this hypothesis, using cultured vascular smooth muscle cells (VSMCs), we demonstrate RGS5 overexpression inhibits G protein-coupled receptor (GPCR)-mediated hypertrophic responses. The next objective was to determine which physiological agonists directly control RGS5 expression in VSMCs. GPCR agonists failed to directly regulate RGS5 mRNA expression; however, platelet-derived growth factor (PDGF) acutely represses expression. Downregulation of RGS5 results in the induction of migration and the activation of the GPCR-mediated signaling pathways. This stimulation leads to the activation of mitogen-activated protein kinases directly downstream of receptor stimulation, and ultimately VSMC hypertrophy. These results demonstrate that RGS5 expression is a critical mediator of both VSMC contraction and potentially, arterial remodeling.


Subject(s)
Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Platelet-Derived Growth Factor/metabolism , RGS Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism , Signal Transduction , Angiotensin II/metabolism , Animals , Becaplermin , Cell Line , Cell Movement , Gene Expression Regulation , Hypertrophy , Ligands , Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Proto-Oncogene Proteins c-sis , RGS Proteins/deficiency , RGS Proteins/genetics , RNA Interference , Rats , Receptors, G-Protein-Coupled/agonists , Signal Transduction/drug effects , Time Factors , Transfection , Vasoconstriction
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