Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling.

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.

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca Release Units in Developing Cardiomyocytes.

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 release units (CRUs). We tested the hypothesis that expression of the protein BIN1 in hESC-CMs promotes T-tubules formation, facilitates Ca 1.

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate.

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.

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

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.

Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment.

Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) signaling in the heart regulates cardiomyocyte contractility and growth in response to elevated intracellular Ca(2+). The δB isoform of CaMKII is the predominant nuclear splice variant in the adult heart and regulates cardiomyocyte hypertrophic gene expression by signaling to the histone deacetylase HDAC4. However, the role of CaMKIIδ in cardiac progenitor cells (CPCs) has not been previously explored.

Cardiac Stem Cell Hybrids Enhance Myocardial Repair.

Rationale: Dual cell transplantation of cardiac progenitor cells (CPCs) and mesenchymal stem cells (MSCs) after infarction improves myocardial repair and performance in large animal models relative to delivery of either cell population.

Objective: To demonstrate that CardioChimeras (CCs) formed by fusion between CPCs and MSCs have enhanced reparative potential in a mouse model of myocardial infarction relative to individual stem cells or combined cell delivery.

Methods And Results: Two distinct and clonally derived CCs, CC1 and CC2, were used for this study.

Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells.

Phase I clinical trials applying autologous progenitor cells to treat heart failure have yielded promising results; however, improvement in function is modest, indicating a need to enhance cardiac stem cell reparative capacity. Notch signaling plays a crucial role in cardiac development, guiding cell fate decisions that underlie myocyte and vessel differentiation. The Notch pathway is retained in the adult cardiac stem cell niche, where level and duration of Notch signal influence proliferation and differentiation of cardiac progenitors.

Cardiac aging - Getting to the stem of the problem.

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'.

Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells.

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.

Pin1: a molecular orchestrator in the heart.

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.

Stressing on the nucleolus in cardiovascular disease.

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.

Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells.

Autologous c-kit(+) cardiac progenitor cells (CPCs) are currently used in the clinic to treat heart disease. CPC-based regeneration may be further augmented by better understanding molecular mechanisms of endogenous cardiac repair and enhancement of pro-survival signaling pathways that antagonize senescence while also increasing differentiation. The prolyl isomerase Pin1 regulates multiple signaling cascades by modulating protein folding and thereby activity and stability of phosphoproteins.

CENP-A is essential for cardiac progenitor cell proliferation.

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.

Rejuvenation of human cardiac progenitor cells with Pim-1 kinase.

Rationale: Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells.

Autophagy plays an essential role in mediating regression of hypertrophy during unloading of the heart.

Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading.

Increased mitotic rate coincident with transient telomere lengthening resulting from pim-1 overexpression in cardiac progenitor cells.

Cardiac regeneration following myocardial infarction rests with the potential of c-kit+ cardiac progenitor cells (CPCs) to repopulate damaged myocardium. The ability of CPCs to reconstitute the heart is restricted by patient age and disease progression. Increasing CPC proliferation, telomere length, and survival will improve the ability of autologous CPCs to be successful in myocardial regeneration.

Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart?

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.

Silent information regulator 1 protects the heart from ischemia/reperfusion.

Background: Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R).

Methods And Results: Protein and mRNA expression of Sirt1 is significantly reduced by I/R.

Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes.

Rationale: autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood.

Objective: we investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy.

Oxidative stress stimulates autophagic flux during ischemia/reperfusion.

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.

Nicotinamide phosphoribosyltransferase regulates cell survival through autophagy in cardiomyocytes.

Nicotinamide adenine dinucleotide (NAD(+)) acts as a transfer molecule for electrons, thereby acting as a key cofactor for energy production. NAD(+) also serves as a substrate for cellular enzymes, including poly (ADPribose) polymerase (PARP)-1 and Sirt1. Activation of PARP-1 by DNA damage depletes the cellular pool of NAD(+), leading to necrotic cell death.

Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes.

Rationale: NAD+ acts not only as a cofactor for cellular respiration but also as a substrate for NAD(+)-dependent enzymes, such as Sirt1. The cellular NAD+ synthesis is regulated by both the de novo and the salvage pathways. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the salvage pathway.