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1.
Pharmacol Res ; 103: 13-6, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26563999

ABSTRACT

During cardiac aging, DNA damage and environmental stressors contribute to telomeric shortening and human cardiac progenitor cells acquire a senescent phenotype that leads to decreased stem cell function. Reversion of this phenotype through genetic modification is essential to advance regenerative therapy. Studies in the cardiac specific overexpression and subcellular targeting of Pim1 kinase demonstrate its influence on regeneration, proliferation, survival, metabolism and senescence. The cardioprotective effects of Pim1 modification can be picked apart and enhanced by targeting the kinase to distinct subcellular compartments, allowing for selection of specific phenotypic traits after molecular modification. In this perspective, we examine the therapeutic implications of Pim1 to encourage the personalization of cardiac regenerative therapy.


Subject(s)
Heart/physiology , Myocardium/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Regeneration , Animals , Humans , Precision Medicine
2.
J Biol Chem ; 290(22): 13935-47, 2015 May 29.
Article in English | MEDLINE | ID: mdl-25882843

ABSTRACT

Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence. Adult hCPCs isolated from patients undergoing left ventricular assist device implantation were engineered to overexpress Pim1 throughout the cell (PimWT) or targeted to either mitochondrial (Mito-Pim1) or nuclear (Nuc-Pim1) compartments. Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated ß-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs. Alternately, Mito-Pim1 enhances survival by increasing expression of Bcl-2 and Bcl-XL and decreasing cell death after H2O2 treatment, thereby preserving mitochondrial integrity superior to PimWT. Mito-Pim1 increases the proliferation rate by up-regulation of cell cycle modulators Cyclin D, CDK4, and phospho-Rb. Optimal stem cell traits such as proliferation, survival, and increased youthful properties of aged hCPCs are enhanced after targeted Pim1 localization to mitochondrial or nuclear compartments. Targeted Pim1 overexpression in hCPCs allows for selection of the desired phenotypic properties to overcome patient variability and improve specific stem cell characteristics.


Subject(s)
Gene Expression Regulation , Heart/physiology , Proto-Oncogene Proteins c-pim-1/metabolism , Stem Cells/metabolism , Apoptosis , Cell Cycle , Cell Nucleus/metabolism , Cell Proliferation , Cell Survival , Cellular Senescence , Green Fluorescent Proteins/metabolism , Heart Failure , Heart Ventricles/metabolism , Humans , Lentivirus/metabolism , Mitochondria/metabolism , Myocardium/cytology , Myocardium/metabolism , Phenotype , Regeneration , Stem Cells/cytology , Subcellular Fractions/metabolism , beta-Galactosidase/metabolism
3.
J Am Coll Cardiol ; 65(2): 133-47, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25593054

ABSTRACT

BACKGROUND: Functional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy in elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency. OBJECTIVES: This study sought to demonstrate that NS preserves characteristics associated with "stemness" in CPCs and antagonizes myocardial senescence and aging. METHODS: CPCs isolated from human fetal (fetal human cardiac progenitor cell [FhCPC]) and adult failing (adult human cardiac progenitor cell [AhCPC]) hearts, as well as young (young cardiac progenitor cell [YCPC]) and old mice (old cardiac progenitor cell [OCPC]), were studied for senescence characteristics and NS expression. Heterozygous knockout mice with 1 functional allele of NS (NS+/-) were used to demonstrate that NS preserves myocardial structure and function and slows characteristics of aging. RESULTS: NS expression is decreased in AhCPCs relative to FhCPCs, correlating with lowered proliferation potential and shortened telomere length. AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16. CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53. Mechanistically, NS induction correlates with Pim-1 kinase-mediated stabilization of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology, and antagonizes senescence, thereby preserving phenotypic properties of "stemness." Early cardiac aging with a decline in cardiac function, an increase in senescence markers p53 and p16, telomere attrition, and accompanied CPC exhaustion is evident in NS+/- mice. CONCLUSIONS: Youthful properties and antagonism of senescence in CPCs and the myocardium are consistent with a role for NS downstream from Pim-1 signaling that enhances cardiac regeneration.


Subject(s)
Carrier Proteins/biosynthesis , Cellular Senescence/physiology , Myocardium/cytology , Nuclear Proteins/biosynthesis , Rejuvenation/physiology , Stem Cells/cytology , Animals , Cell Differentiation , Cells, Cultured , GTP-Binding Proteins , Humans , Male , Mice , Mice, Knockout , Myocardium/metabolism , RNA-Binding Proteins , Stem Cells/metabolism
4.
Circ Res ; 115(3): 376-87, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-24916111

ABSTRACT

RATIONALE: The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention because Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight about cardiac mitochondrial biology and the aging phenotype. OBJECTIVE: To demonstrate that myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function. METHODS AND RESULTS: Cardiac myocyte senescence was evident at 3 months in Pim triple knockout mice, where all 3 isoforms of Pim kinase family members are genetically deleted. Cellular hypertrophic remodeling and fetal gene program activation were followed by heart failure at 6 months in Pim triple knockout mice. Metabolic dysfunction is an underlying cause of cardiac senescence and instigates a decline in cardiac function. Altered mitochondrial morphology is evident consequential to Pim deletion together with decreased ATP levels and increased phosphorylated AMP-activated protein kinase, exposing an energy deficiency in Pim triple knockout mice. Expression of the genes encoding master regulators of mitochondrial biogenesis, PPARγ (peroxisome proliferator-activated receptor gamma) coactivator-1 α and ß, was diminished in Pim triple knockout hearts, as were downstream targets included in mitochondrial energy transduction, including fatty acid oxidation. Reversal of the dysregulated metabolic phenotype was observed by overexpressing c-Myc (Myc proto-oncogene protein), a downstream target of Pim kinases. CONCLUSIONS: Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics.


Subject(s)
Aging, Premature/metabolism , Cardiomegaly/metabolism , Mitochondria, Heart/metabolism , Myocytes, Cardiac/metabolism , Proto-Oncogene Proteins c-pim-1/genetics , Aging, Premature/genetics , Aging, Premature/pathology , Animals , Cardiomegaly/pathology , Cell Line, Transformed , Cell Respiration/genetics , Cellular Senescence/genetics , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Mice , Mice, Knockout , Myocytes, Cardiac/cytology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Proto-Oncogene Mas , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , RNA, Small Interfering/genetics , Rats , Telomere/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
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