Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload (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
Pim-1 regulates cardiomyocyte survival downstream of Akt
Nature Medicine, 2007
The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X L protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.
Cardiac hypertrophy is enhanced in PPAR -/- mice in response to chronic pressure overload
Cardiovascular Research, 2008
Time for primary review: 37 days Aims Peroxisome proliferator-activated receptor-a (PPARa) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPARa modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARa aggravates the cardiac hypertrophic response to pressure overload. Methods and results Male PPARa2/2 and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (LV) wall thickness in PPARa2/2 than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPARa2/2 mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, a-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-a, cyclo-oxygenase-2) marker genes were higher in PPARa2/2 than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPARa2/2 mice, but were not further compromised by TAC. Conclusion The present findings show that the absence of PPARa results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPARa exerts salutary effects during cardiac hypertrophy.
Cardiac hypertrophy is enhanced in PPARa2/2 mice in response to chronic pressure overload
2008
Aims Peroxisome proliferator-activated receptor-a (PPARa) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPARa modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARa aggravates the cardiac hypertrophic response
2003
During cardiac hypertrophy individual cardiac myocytes increase in size, which is accompanied by augmented protein synthesis and selective induction of a subset of genes. These phenotypic changes of myocytes are a result from altered intracellular signaling mechanisms and molecules. B-type natriuretic peptide (BNP) gene was selected as a target gene for the study of cardiac signaling mechanisms, since it is activated by mechanical, neural and humoral stimuli during myocyte hypertrophy. To generate hypertrophy of cardiac myocytes, neonatal rat cardiac myocytes were subjected to exogenous hypertrophic agonists such as endothelin-1 (ET-1) or to cyclic mechanical stretch. The role and regulation of transcription factors were studied by utilizing promoter analysis together with site-specific mutations and measurement of DNA binding activity and phosphorylation. GATA-4 mediated signaling was inhibited by blocking DNA binding with decoy oligonucleotides or by decreasing GATA-4 synthesis via adenoviral antisense delivery. ET-1 activated GATA-4 via serine residue phosphorylation, and this effect was mediated via p38 kinase. Similarly, GATA-4 binding activity was increased by ET-1 and mechanical stretch, but it was essential for activation of BNP gene only in the latter stimulation. Importantly, downregulation of GATA-4 protein levels prevented mechanical stretch induced hypertrophy of cardiac myocytes. In contrast, separate mechanism for an ET-1 specific signaling was composed of p38 kinase regulated ETS-like transcription factor-1 (Elk-1). Finally, the effect of mechanical stretch on endogenous endothelin-1 (ET-1) synthesis in cardiac cells was studied. Intrinsic ET-1 synthesis was activated in stretched cardiac myocytes, yet the levels of ET-1 were relatively low. This work suggests that GATA-4 transcription factor is required for mechanical stretch mediated hypertrophic program, and Elk-1 may act as a downstream effector of ET-1 in cardiac myocytes. Taken together, induction of ET-1 and BNP genes as well as activation of GATA-4 and Elk-1 transcription factors are regulated via a network of mitogen activated protein kinase pathways.
Cell, 2004
that relies on protein interactions to regulate PDE3B activity and negatively modulates cardiac contractility. Cardiac function is controlled by G protein-coupled re-San Giovanni Battista Hospital ceptors (GPCRs), plasma membrane proteins that exert 10126 Torino their function by triggering numerous intracellular sig-3 Department of Neurocardiology naling pathways including the activation of class I phos-Neuromed Institute phoinositide 3-kinases (PI3Ks) (Rockman et al., 2002). Via Atinense 18 These enzymes are characterized by both lipid and pro-86077 Pozzilli (Isernia) tein kinase activity (Vanhaesebroeck et al., 2001). On Italy lipids, they catalyze the addition of a phosphate group 4 Department of Pharmacology at the D3 position of the phosphatidylinositol (PtdIns) University of Washington ring (Cantley, 2002). PI3Ks are characterized by a 110 P.O. Box 357280 kDa catalytic subunit (p110) and are divided into the Seattle, Washington 98195 subclasses IA and IB. Class IA consists of p110␣, , 5 Research Unit Molecular Cell Biology and ␦ catalytic subunits, which associate with the p85 University Hospital Jena family of adaptor proteins and are essential for tyrosine Drackendorfer Strasse 1 kinase receptor signaling (Wymann et al., 2003b). Class D-07747 Jena IB is composed by the single p110␥ catalytic subunit Germany (PI3K␥), which is activated by GPCRs by direct binding 6 Department of Clinical and Biological Sciences of G ␥ subunits or via the regulatory subunit p101 (Ste-University of Basel phens et al., 1997; Stoyanov et al., 1995). Receptor-Klingelbergstrasse 23 dependent stimulation of PI3Ks causes the production CH-4301 Basel of PtdIns(3,4,5)P 3 that serves as a docking site for pro-Switzerland teins carrying the pleckstrin homology domains like the 7 Department of Experimental Medicine kinase PKB/Akt. However, class IB PI3K␥ also directly and Pathology phosphorylates MEK and induces MAPK Erk activation University of Rome "La Sapienza" (Bondeva et al., 1998). Rome While p110␣ and  are ubiquitously expressed, p110␦ Italy is predominantly
AJP: Heart and Circulatory Physiology, 2008
The PI3K signaling pathway regulates multiple cellular processes including cell survival/apoptosis and growth. In the cardiac context, PI3Kα plays important roles in cardiac growth. We have shown that cardiac PI3K activity is highly regulated during development, with the highest levels found during the fetal-neonatal transition period and the lowest levels in the adult. There is a close relationship between cardiomyocyte proliferation and cardiac PI3K activity. In adult transgenic mice, however, prolonged constitutive activation of PI3Kα in the heart results in hypertrophy. To develop a strategy to allow temporally controlled overexpression of cardiac PI3Kα, we engineered a tetracycline (tet) transactivator (tTA) tet-off controlled transgenic mouse line with conditional overexpression of a cardiac-specific fusion protein of the SH2 domain of p85 and p110α. Cardiac PI3K activity and Akt phosphorylation were significantly increased in adult mice after transgene induction following removal of doxycycline for 2 weeks. Heart weight to body weight ratio was not changed and there were no signs of cardiomyopathy. Overexpression of PI3Kα resulted in increased left ventricular (LV) developed pressure, LV dP/dt max and LV dP/dt min, but not heart rate, as assessed in Langendorff hearts.
Journal of Molecular and Cellular Cardiology, 2008
AMP-activated protein kinase (AMPK), is an important regulator of cardiac metabolism, but it's role is not clearly understood in pressure overload induced hypertrophy. In addition, the relationship between AMPK and other important protein kinases such as p38 MAP kinase, Akt and Pim-1 are unclear. Thus we studied the time course of AMPK activity and phosphorylation of its α-subunit during the development of cardiac hypertrophy. In parallel, we examined the expression and activation of key kinases known to be involved in cardiac hypertrophy that could interact with AMPK (i.e. p38 MAP kinase, Akt and Pim-1). Male C57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery and the hearts were harvested 2, 4, 6 and 8 weeks later. Despite significant left ventricular (LV) hypertrophy, LV dilation and impaired LV contractile function at all time points in TAC compared to sham mice, the activity and phosphorylation of AMPK were similar to sham. In contrast, p38 and Pim-1 protein expression were transiently increased in TAC mice at 2 and 4 weeks and at 2, 4 and 6 weeks, respectively. In addition, p38 activation by phosphorylation was also transiently increased at 2 to 6 weeks. There were no differences between sham and TAC mice in p38, Akt or Pim-1 at 8 weeks. In conclusion, TAC resulted in a transient upregulation in the expression of p38 and Pim-1 despite no activation of AMPK or Akt.
Molecular targets and regulators of cardiac hypertrophy
Pharmacological Research, 2010
Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli. It enables myocytes to increase their work output, which improves cardiac pump function. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world. A number of signaling modulators that influence gene expression, apoptosis, cytokine release and growth factor signaling, etc. are known to regulate heart. By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed. This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy. In this review, we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin, cGMP, NFAT, natriuretic peptides, histone deacetylase, IL-6 cytokine family, Gq/G11 signaling, PI3K, MAPK pathways, Na/H exchanger, RAS, polypeptide growth factors, ANP, NO, TNF-␣, PPAR and JAK/STAT pathway, microRNA, Cardiac angiogenesis and gene mutations in adult heart. Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy. The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy, with special emphasis on novel researches and investigations.