PIM1-minicircle as a therapeutic treatment for myocardial infarction

Liu, Nan; Wang, Bingyan; Broughton, Kathleen M.; Álvarez, Roberto Baelo; Siddiqi, Sailay; Loaiza, Rebeca; Nguyen, Nicky; Quijada, Pearl; Gude, Natalie; Sussman, Mark A.

doi:10.1371/journal.pone.0173963

Cited by 13 publications

(8 citation statements)

References 45 publications

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“…The cardioprotective role of PIM1 is well established [ 8 , 9 , 10 , 29 , 30 , 31 ] but the involvement of c-Kit in PIM1-mediated cardioprotection has not been elucidated. The involvement of c-Kit in PIM1-mediated cardioprotection was assessed in cardiomyocytes subjected to oxidative stress following treatment with imatinib, an inhibitor of c-Kit activity [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

Ebeid

Firouzi

Esquer

et al. 2020

Cells

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Enhancing cardiomyocyte survival is crucial to blunt deterioration of myocardial structure and function following pathological damage. PIM1 (Proviral Insertion site in Murine leukemia virus (PIM) kinase 1) is a cardioprotective serine threonine kinase that promotes cardiomyocyte survival and antagonizes senescence through multiple concurrent molecular signaling cascades. In hematopoietic stem cells, PIM1 interacts with the receptor tyrosine kinase c-Kit upstream of the ERK (Extracellular signal-Regulated Kinase) and Akt signaling pathways involved in cell proliferation and survival. The relationship between PIM1 and c-Kit activity has not been explored in the myocardial context. This study delineates the interaction between PIM1 and c-Kit leading to enhanced protection of cardiomyocytes from stress. Elevated c-Kit expression is induced in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1. Co-immunoprecipitation and proximity ligation assay reveal protein–protein interaction between PIM1 and c-Kit. Following treatment with Stem Cell Factor, PIM1-overexpressing cardiomyocytes display elevated ERK activity consistent with c-Kit receptor activation. Functionally, elevated c-Kit expression confers enhanced protection against oxidative stress in vitro. This study identifies the mechanistic relationship between PIM1 and c-Kit in cardiomyocytes, demonstrating another facet of cardioprotection regulated by PIM1 kinase.

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Section: Resultsmentioning

confidence: 99%

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

Ebeid

Firouzi

Esquer

et al. 2020

Cells

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“…S3). Several studies have reported that PIM1 is a cardioprotective gene 45,46 . Moreover, PIM1 restores senescence in c-Kit + hCPCs 47 .…”

Section: Molecular Mechanism Of Prolonged Rapamycin Treatment In Senementioning

confidence: 99%

Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells

et al. 2020

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The mammalian target of rapamycin (mTOR) signaling pathway efficiently regulates the energy state of cells and maintains tissue homeostasis. Dysregulation of the mTOR pathway has been implicated in several human diseases. Rapamycin is a specific inhibitor of mTOR and pharmacological inhibition of mTOR with rapamycin promote cardiac cell generation from the differentiation of mouse and human embryonic stem cells. These studies strongly implicate a role of sustained mTOR activity in the differentiating functions of embryonic stem cells; however, they do not directly address the required effect for sustained mTOR activity in human cardiac progenitor cells. In the present study, we evaluated the effect of mTOR inhibition by rapamycin on the cellular function of human cardiac progenitor cells and discovered that treatment with rapamycin markedly attenuated replicative cell senescence in human cardiac progenitor cells (hCPCs) and promoted their cellular functions. Furthermore, rapamycin not only inhibited mTOR signaling but also influenced signaling pathways, including STAT3 and PIM1, in hCPCs. Therefore, these data reveal a crucial function for rapamycin in senescent hCPCs and provide clinical strategies based on chronic mTOR activity.

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“…Similar results were also observed when using murine CPCs [207] but these earlier studies relied largely on viral delivery methods to induce PIM1 overexpression. In an alternative strategy, a non-viral modified plasmid-minicircle (MC) was used as a vehicle to deliver PIM1 into mouse CPCs (mCPCs) in vitro and the myocardium in vivo [208]. Mice with PIM1-MC injection showed increased protection compared to control groups measured by ejection fraction at 3-and 7-days post injury, supporting the potential of a non-cell based therapeutic approach for treatment of ischemic heart disease and MI.…”

Section: Genetic Engineering With Pim1mentioning

confidence: 99%

Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials

Barreto

Hamel

Schiatti

et al. 2019

Cells

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Cardiac Progenitor Cells (CPCs) show great potential as a cell resource for restoring cardiac function in patients affected by heart disease or heart failure. CPCs are proliferative and committed to cardiac fate, capable of generating cells of all the cardiac lineages. These cells offer a significant shift in paradigm over the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes owing to the latter’s inability to recapitulate mature features of a native myocardium, limiting their translational applications. The iPSCs and direct reprogramming of somatic cells have been attempted to produce CPCs and, in this process, a variety of chemical and/or genetic factors have been evaluated for their ability to generate, expand, and maintain CPCs in vitro. However, the precise stoichiometry and spatiotemporal activity of these factors and the genetic interplay during embryonic CPC development remain challenging to reproduce in culture, in terms of efficiency, numbers, and translational potential. Recent advances in biomaterials to mimic the native cardiac microenvironment have shown promise to influence CPC regenerative functions, while being capable of integrating with host tissue. This review highlights recent developments and limitations in the generation and use of CPCs from stem cells, and the trends that influence the direction of research to promote better application of CPCs.

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PIM1-minicircle as a therapeutic treatment for myocardial infarction

Cited by 13 publications

References 45 publications

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression

Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells

Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials

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