Pim-1 regulates cardiomyocyte survival downstream of Akt (original) (raw)
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Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling
Journal of Molecular and Cellular Cardiology, 2011
Stem cells mediate tissue repair throughout the lifespan of an organism. However, the ability of stem cells to mitigate catastrophic damage, such as that sustained after major myocardial infarction is inadequate to rebuild the heart and restore functional capacity. However, capitalizing on the ability of these cells to attenuate damage in the myocardium, various maneuvers that enhance repair mechanisms to improve cardiac structure and function after injury are being investigated. These studies have led to discovery of various factors that mediate cardioprotection and enhance endogenous repair by 1) salvaging surviving myocardium, 2) promoting homing of stem cells and 3) increasing survival and proliferation of stem cell populations at the site of injury. Herein we report upon a downstream target of Akt kinase, named Pim-1, which promotes cardioprotective signaling and enhances cardiac structure and function after pathological injury. The compilation of studies presented here supports use of Pim-1 to enhance long-term myocardial repair after pathological damage. I. Pim-1 Kinase The use of cardioprotective molecules to mitigate pathologic injury has been extensively studied in the myocardial context, particularly with respect to the serine/threonine kinase known as Akt [1,2]. In comparison the cardioprotective actions of Pim-1, a downstream target of Akt activity with substrate specificities similar in many respects to Akt have just begun to be investigated. Pim-1 kinase was initially identified as the Proviral Insertion site for Moloney Murine Leukemia Virus in mouse T cell lymphomas [3]. Pim-1 belongs to a family of constitutively active serine/threonine kinases, including Pim-2 and-3 [4], which have the ability to auto-phosphorylate at Ser-190, Thr-205 and Ser-4 [5-7]. Pim-1 expression promotes cell cycle progression, proliferation, and survival in the context of hematopoiesis and cancer [8,9] Seminal studies describing the function of Pim-1 in vivo were conducted in the hematopoetic system in the context of lymphomagenesis. Initial studies investigating Pim-1 demonstrated that B cell lymphomas [10], erythroleukemias [11], and T cell lymphomas [12,13] all carry elevated levels of Pim-1. Interestingly, subsequent studies revealed that overexpression of Pim-1 alone is not sufficient to induce transformation [14,15]. Rather, the cooperation of other oncogenic stimuli must also be present, including BCR/ABL [16], c-Myc, bmi-1 and gfi-1 [17,18]. High incidence of overexpression in lymphomas as well as some endogenous expression in healthy hematopoetic cells led to an investigation into other cell types that
Journal of Molecular and Cellular Cardiology, 2013
Objectives-The serine/threonine kinase Pim-1 was recently identified as a cardiomyocyte survival regulator downstream of Akt. The present study aims to examine Pim-1 activity and its association with the post MI remodeling myocardium in a clinically relevant large animal model. Methods-Apical myocardial infarction of approximately 25% left ventricular mass was created in an ovine model. Regional post-infarction deformation of the left ventricle was monitored by sonomicrometry and quantified using areal remodeling strain (i.e., areal expansion). Myocardial tissues were harvested at 12 weeks from the adjacent and remote regions of the infarct for analysis of Pim-1 mediated survival signaling proteins as well as apoptotic activity. Results-The cDNA coding sequences of two ovine Pim-1 kinase isoforms, 44 and 33 kDa, were identified. Both isoforms were detected in heart tissue and the overall Pim-1 expression was found to be tightly controlled at multiple molecular levels. Pim-1 as well as the Pim-1 mediated survival signaling proteins Bcl-2, Bcl-xL, and phospho-Bad (Ser112), were upregulated in the adjacent region at 12 weeks post-infarction and their expression correlated positively with the degree of the remodeling, which was accompanied by significant upregulations of the PP2A/BAD mediated apoptotic signaling proteins. However these upregulations were imbalanced, such that p-BAD (Ser112)/BAD decreased in the adjacent region of the infarcted hearts. Apoptotic activity also increased with remodeling strain. Conclusions-Despite an observed intrinsic upregulation of survival proteins, the imbalanced activation of apoptotic pathways resulted in evident apoptosis in the adjacent region.
PIM1 Promotes Survival of Cardiomyocytes by Upregulating c-Kit Protein Expression
Cells, 2020
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...
Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival
Journal of Biological Chemistry, 2006
The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[ 3 H]deoxyglucose uptake and metabolism. In contrast, akt2 ؊/؊ mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2 ؊/؊ mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2 ؊/؊ hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival. Cardiac growth and metabolism are coordinated through the integration of a complex array of extracellular and intracellular signals. Much recent work suggests that the Akt family of intracellular serine-threonine kinases regulates both cardiac growth and metabolism (1-3). The Akt family of serine-threonine kinases consists of three isoforms, Akt1, Akt2, and Akt3, each encoded by distinct, highly conserved genes. All three isoforms are expressed in the myocardium, although Akt1 and Akt2 comprise the vast majority of total Akt protein in the heart (2). Examination of numerous experimental models implicates both Akt1 and Akt3 in regulating pathological and physiological hypertrophy (4-6). Indeed, the hypothesis that the phosphatidylinositol 3-kinase (PI3K) 3 ␣-Akt1 cascade mediates physiological cardiac growth is now well founded (7). Cardiacspecific expression of constitutively active Akt1 (myristoylated Akt1) in transgenic mice results in massive cardiac hypertrophy and fibrosis consistent with pathological hypertrophy (4), and nuclear localization of Akt1 was recently shown to augment ventricular function and contractility (8). A comparable phenotype was observed in response to cardiac overexpression of activated Akt3, whereas no observable cardiac growth defects were detectable in Akt3-deficient mice at baseline (6). Akt family members are also key regulators of cellular metabolism. Indeed, GLUT4 translocation to the plasma membrane is a wortmannin-sensitive process (9), and Akt2-mediated phosphorylation of the syntaxin interacting protein (synip) results in docking and fusion of GLUT4-containing vesicles with the plasma membrane (10). Akt family members promote glycogen synthesis through phosphorylation and inhibition of glycogen synthase kinase 3 (GSK3), which itself inhibits glycogen synthesis (11). GSK3 phosphorylation results in the augmentation of glycogen synthesis, whereas Akt activation antagonizes the AMP-activated protein kinase (12), a key mediator of glycogenolysis and lipolysis. In addition, Akt kinases inhibit fatty acid metabolism by phosphorylating and inhibiting FOXO-1, a forkhead family transcription factor that positively modulates fatty acid oxidative gene expression (13). Although the role of Akt family members in cardiac growth and metabolism has been widely studied, the role of Akt2 in the development of physiological and pathological cardiac hypertrophy is unknown. Additionally, the role of individual Akt family members in the regulation of cardiac metabolism remains unexplored. In the current study, an Akt2 loss-of-function murine model was utilized to assess the role of Akt2 in cardiac growth, metabolism, and cardiomyocyte survival. Here, we show that Akt2 is dispensable in the development of cardiac hypertrophy in response to a variety of physiological and pathological provocative stimuli. Conversely, we demonstrate that
Proceedings of the National Academy of Sciences, 2008
Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca 2؉ transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels.
2010
Background—The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear. Methods and Results—We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer
Short-Term Akt Activation in Cardiac Muscle Cells Improves Contractile Function in Failing Hearts
The American Journal of Pathology, 2012
Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we previously showed that short-term Akt activation induces a physiological form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling transiently was activated in murine hearts with impaired contractility, induced by pressure overload or doxorubicin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt activation improves contractile function independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile function in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure. (Am J Pathol 2012, 181:1969 -1976; http://dx.doi.
Journal of the American College of Cardiology, 2016
BACKGROUND-Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit + cardiac stem cell (CSC) enhances their cardioreparative properties. OBJECTIVES-We sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). METHODS-Human CSCs (hCSCs, n = 10), hckit + CSCs overexpressing Pim1 (Pim1 + ; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration.