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Article ; Online: Cardiac aging - Getting to the stem of the problem.

Hariharan, Nirmala / Sussman, Mark A

Journal of molecular and cellular cardiology

2015 Volume 83, Page(s) 32–36

Abstract: Cardiac aging is a heterogeneous process caused by a combination of stochastic events which manifests as loss of structure and function in the heart, however several recent studies draw attention to aging being primarily a stem cell problem. This review ... ...

Abstract	Cardiac aging is a heterogeneous process caused by a combination of stochastic events which manifests as loss of structure and function in the heart, however several recent studies draw attention to aging being primarily a stem cell problem. This review summarizes findings in support of the "stem cell hypothesis of aging" and discusses the impact of age on cardiac stem cells and the niche. This article is part of a Special Issue entitled 'CV Aging'.
MeSH term(s)	Aging/metabolism ; Aging/pathology ; Animals ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Cardiomyopathies/pathology ; Cardiomyopathies/therapy ; Cell Differentiation ; Cell Proliferation ; Humans ; Mice ; Myocardium/metabolism ; Myocardium/pathology ; Species Specificity ; Stem Cell Niche/physiology ; Stem Cell Transplantation ; Stem Cells/metabolism ; Stem Cells/pathology
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2015.04.008
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Article ; Online: Pin1: a molecular orchestrator in the heart.

Hariharan, Nirmala / Sussman, Mark A

Trends in cardiovascular medicine

2014 Volume 24, Issue 6, Page(s) 256–262

Abstract: Pin1 is an evolutionarily conserved peptidyl-prolyl isomerase that binds and changes the three-dimensional conformation of specific phospho-proteins. By regulating protein structure and folding, Pin1 affects the stability, interaction, and activity of a ... ...

Abstract	Pin1 is an evolutionarily conserved peptidyl-prolyl isomerase that binds and changes the three-dimensional conformation of specific phospho-proteins. By regulating protein structure and folding, Pin1 affects the stability, interaction, and activity of a broad spectrum of target proteins, thus impacting upon diverse cellular processes. This review discusses the pivotal role Pin1 plays in regulating cardiac pathophysiology by functioning as a "molecular orchestrator" of a myriad of signal transduction pathways in the heart.
MeSH term(s)	Cell Physiological Phenomena ; Humans ; Myocardium/metabolism ; Peptidylprolyl Isomerase/metabolism ; Phosphoproteins/metabolism ; Phosphorylation/physiology ; Signal Transduction
Chemical Substances	Phosphoproteins ; Peptidylprolyl Isomerase (EC 5.2.1.8)
Language	English
Publishing date	2014-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1097434-9
ISSN	1873-2615 ; 1050-1738
ISSN (online)	1873-2615
ISSN	1050-1738
DOI	10.1016/j.tcm.2014.05.010
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Zs.A 3419: Show issues

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Article: Stressing on the nucleolus in cardiovascular disease.

Hariharan, Nirmala / Sussman, Mark A

Biochimica et biophysica acta

2013 Volume 1842, Issue 6, Page(s) 798–801

Abstract: The nucleolus is a multifunctional organelle with multiple roles involving cell proliferation, growth, survival, ribosome biogenesis and stress response signaling. Alteration of nucleolar morphology and architecture signifies an early response to ... ...

Abstract	The nucleolus is a multifunctional organelle with multiple roles involving cell proliferation, growth, survival, ribosome biogenesis and stress response signaling. Alteration of nucleolar morphology and architecture signifies an early response to increased cellular stress. This review briefly summarizes nucleolar response to cardiac stress signals and details the role played by nucleolar proteins in cardiovascular pathophysiology. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
MeSH term(s)	Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/physiopathology ; Cell Nucleolus/genetics ; Cell Nucleolus/metabolism ; Cell Proliferation ; Fibrillins ; Humans ; Microfilament Proteins/metabolism ; Nuclear Proteins/metabolism ; Nucleophosmin ; Phosphoproteins/metabolism ; RNA-Binding Proteins/metabolism ; Signal Transduction ; Nucleolin
Chemical Substances	Fibrillins ; Microfilament Proteins ; Nuclear Proteins ; Phosphoproteins ; RNA-Binding Proteins ; Nucleophosmin (117896-08-9)
Language	English
Publishing date	2013-10-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2013.09.016
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Uc I Zs.247: Show issues

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Article ; Online: Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase.

Samse, Kaitlen / Hariharan, Nirmala / Sussman, Mark A

Pharmacological research

2016 Volume 103, Page(s) 13–16

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 ... ...

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.
MeSH term(s)	Animals ; Heart/physiology ; Humans ; Myocardium/metabolism ; Precision Medicine ; Proto-Oncogene Proteins c-pim-1/metabolism ; Regeneration
Chemical Substances	PIM1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1)
Language	English
Publishing date	2016-01
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2015.11.001
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Zs.A 721: Show issues

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Article ; Online: Oxidative stress stimulates autophagic flux during ischemia/reperfusion.

Hariharan, Nirmala / Zhai, Peiyong / Sadoshima, Junichi

Antioxidants & redox signaling

2011 Volume 14, Issue 11, Page(s) 2179–2190

Abstract: Autophagy is a bulk degradation process in which cytosolic proteins and organelles are degraded through lysosomes. To evaluate autophagic flux in cardiac myocytes, we generated adenovirus and cardiac-specific transgenic mice harboring tandem fluorescent ... ...

Abstract	Autophagy is a bulk degradation process in which cytosolic proteins and organelles are degraded through lysosomes. To evaluate autophagic flux in cardiac myocytes, we generated adenovirus and cardiac-specific transgenic mice harboring tandem fluorescent mRFP-GFP-LC3. Starvation significantly increased the number of mRFP-GFP-LC3 dots representing both autophagosomes and autolysosomes per cell, suggesting that autophagic flux is increased in cardiac myocytes. H(2)O(2) significantly increased autophagic flux, which was attenuated in the presence of N-2-mercaptopropionyl glycine (MPG), an antioxidant, suggesting that oxidative stress stimulates autophagy in cardiac myocytes. Myocardial ischemia/reperfusion (I/R) increased both autophagosomes and autolysosomes, thereby increasing autophagic flux. Treatment with MPG attenuated I/R-induced increases in oxidative stress, autophagic flux, and Beclin-1 expression, accompanied by a decrease in the size of myocardial infarction (MI)/area at risk (AAR), suggesting that oxidative stress plays an important role in mediating autophagy and myocardial injury during I/R. MI/AAR after I/R was significantly reduced in beclin1(+/-) mice, whereas beclin1(+/-) mice treated with MPG exhibited no additional reduction in the size of MI/AAR after I/R. These results suggest that oxidative stress plays an important role in mediating autophagy during I/R, and that activation of autophagy through oxidative stress mediates myocardial injury in response to I/R in the mouse heart.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Apoptosis Regulatory Proteins/genetics ; Autophagy ; Beclin-1 ; Cell Culture Techniques ; Cells, Cultured ; Hydrogen Peroxide/metabolism ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Transgenic ; Microtubule-Associated Proteins/metabolism ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/prevention & control ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Oxidative Stress ; Rats ; Rats, Wistar ; Starvation ; Tiopronin/pharmacology
Chemical Substances	Antioxidants ; Apoptosis Regulatory Proteins ; Beclin-1 ; Becn1 protein, mouse ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins ; Hydrogen Peroxide (BBX060AN9V) ; Tiopronin (C5W04GO61S)
Language	English
Publishing date	2011-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2010.3488
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Zs.A 5488: Show issues

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Article ; Online: CENP-A is essential for cardiac progenitor cell proliferation.

McGregor, Michael / Hariharan, Nirmala / Joyo, Anya Y / Margolis, Robert L / Sussman, Mark A

Cell cycle (Georgetown, Tex.)

2013 Volume 13, Issue 5, Page(s) 739–748

Abstract: Centromere protein A (CENP-A) is a homolog of histone H3 that epigenetically marks the heterochromatin of chromosomes. CENP-A is a critical component of the cell cycle machinery that is necessary for proper assembly of the mitotic spindle. However, the ... ...

Abstract	Centromere protein A (CENP-A) is a homolog of histone H3 that epigenetically marks the heterochromatin of chromosomes. CENP-A is a critical component of the cell cycle machinery that is necessary for proper assembly of the mitotic spindle. However, the role of CENP-A in the heart and cardiac progenitor cells (CPCs) has not been previously studied. This study shows that CENP-A is expressed in CPCs and declines with age. Silencing CENP-A results in a decreased CPC growth rate, reduced cell number in phase G 2/M of the cell cycle, and increased senescence associated β-galactosidase activity. Lineage commitment is not affected by CENP-A silencing, suggesting that cell cycle arrest induced by loss of CENP-A is a consequence of senescence and not differentiation. CENP-A knockdown does not exacerbate cell death in undifferentiated CPCs, but increases apoptosis upon lineage commitment. Taken together, these results indicate that CPCs maintain relatively high levels of CENP-A early in life, which is necessary for sustaining proliferation, inhibiting senescence, and promoting survival following differentiation of CPCs.
MeSH term(s)	Animals ; Autoantigens/genetics ; Autoantigens/metabolism ; Cell Death/genetics ; Cell Differentiation ; Cell Proliferation ; Cell Survival/genetics ; Cells, Cultured ; Cellular Senescence ; Centromere Protein A ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; G2 Phase Cell Cycle Checkpoints ; Mice ; Myocardium/cytology ; Myocardium/metabolism ; Stem Cells/cytology ; Stem Cells/metabolism
Chemical Substances	Autoantigens ; Cenpa protein, mouse ; Centromere Protein A ; Chromosomal Proteins, Non-Histone
Language	English
Publishing date	2013-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.27549
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Zs.A 5881: Show issues

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Article ; Online: Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart?

Sciarretta, Sebastiano / Hariharan, Nirmala / Monden, Yoshiya / Zablocki, Daniela / Sadoshima, Junichi

Pediatric cardiology

2010 Volume 32, Issue 3, Page(s) 275–281

Abstract: Autophagy is a catabolic process that degrades long-lived proteins and damaged organelles by sequestering them into double membrane structures termed "autophagosomes" and fusing them with lysosomes. Autophagy is active in the heart at baseline and ... ...

Abstract	Autophagy is a catabolic process that degrades long-lived proteins and damaged organelles by sequestering them into double membrane structures termed "autophagosomes" and fusing them with lysosomes. Autophagy is active in the heart at baseline and further stimulated under stress conditions including starvation, ischemia/reperfusion, and heart failure. It plays an adaptive role in the heart at baseline, thereby maintaining cardiac structure and function and inhibiting age-related cardiac abnormalities. Autophagy is activated by ischemia and nutrient starvation in the heart through Sirt1-FoxO- and adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent mechanisms, respectively. Activation of autophagy during ischemia is essential for cell survival and maintenance of cardiac function. Autophagy is strongly activated in the heart during reperfusion after ischemia. Activation of autophagy during reperfusion could be either protective or detrimental, depending on the experimental model. However, strong induction of autophagy accompanied by robust upregulation of Beclin1 could cause autophagic cell death, thereby proving to be detrimental. This review provides an overview regarding both protective and detrimental functions of autophagy in the heart and discusses possible applications of current knowledge to the treatment of heart disease.
MeSH term(s)	Aging/physiology ; Autophagy ; Humans ; Myocardial Ischemia/physiopathology ; Myocardial Reperfusion ; Signal Transduction
Language	English
Publishing date	2010-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	800857-7
ISSN	1432-1971 ; 0172-0643
ISSN (online)	1432-1971
ISSN	0172-0643
DOI	10.1007/s00246-010-9855-x
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Article ; Online: BIN1 Induces the Formation of T-Tubules and Adult-Like Ca

De La Mata, Ana / Tajada, Sendoa / O'Dwyer, Samantha / Matsumoto, Collin / Dixon, Rose E / Hariharan, Nirmala / Moreno, Claudia M / Santana, Luis Fernando

Stem cells (Dayton, Ohio)

2018 Volume 37, Issue 1, Page(s) 54–64

Abstract: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although ... ...

Abstract	Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although they express contractile proteins and have sarcomeres, they do not develop transverse-tubules (T-tubules) with adult-like Ca
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Calcium/metabolism ; Calcium Signaling ; Cell Differentiation ; Humans ; Myocytes, Cardiac/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; BIN1 protein, human ; Nuclear Proteins ; Tumor Suppressor Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1143556-2
ISSN	1549-4918 ; 1066-5099
ISSN (online)	1549-4918
ISSN	1066-5099
DOI	10.1002/stem.2927
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Article ; Online: Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate.

Matsumoto, Collin / Jiang, Yan / Emathinger, Jacqueline / Quijada, Pearl / Nguyen, Nathalie / De La Torre, Andrea / Moshref, Maryam / Nguyen, Jonathan / Levinson, Aimee B / Shin, Minyoung / Sussman, Mark A / Hariharan, Nirmala

Stem cells (Dayton, Ohio)

2018 Volume 36, Issue 6, Page(s) 868–880

Abstract: Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres ... ...

Abstract	Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.
MeSH term(s)	Aging ; Animals ; Autophagy ; Cell Differentiation ; Heart/physiology ; Humans ; Mice ; Stem Cells/metabolism ; Telomere/metabolism ; Telomere Shortening/physiology ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2018-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1143556-2
ISSN	1549-4918 ; 1066-5099
ISSN (online)	1549-4918
ISSN	1066-5099
DOI	10.1002/stem.2793
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Article ; Online: Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling.

Cardiovascular research

2020 Volume 117, Issue 1, Page(s) 201–211

Abstract: Aims: Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes ...

Abstract	Aims: Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes. Methods and results: Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes. Conclusion: Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.
MeSH term(s)	A549 Cells ; Animals ; Cellular Senescence/drug effects ; Humans ; Male ; Mice, Knockout ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/enzymology ; Phosphorylation ; Proto-Oncogene Proteins c-pim-1/genetics ; Proto-Oncogene Proteins c-pim-1/metabolism ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction ; Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; Telomerase/metabolism ; Telomere Homeostasis/drug effects ; Transforming Growth Factor beta1/pharmacology ; Mice
Chemical Substances	Receptors, Transforming Growth Factor beta ; Smad2 Protein ; Smad2 protein, mouse ; Smad3 Protein ; Smad3 protein, mouse ; Transforming Growth Factor beta1 ; PIM1 protein, human (EC 2.7.11.1) ; Pim1 protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1) ; Telomerase (EC 2.7.7.49) ; Tert protein, mouse (EC 2.7.7.49)
Language	English
Publishing date	2020-02-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvaa066
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