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Syed Haq

Publications and source records attributed to Syed Haq.

9 recordsLinked to original sources
PubMed2006

Activation of beta-catenin signaling pathways by classical G-protein-coupled receptors: mechanisms and consequences in cycling and non-cycling cells.

Wnt signaling pathways are some of the most intensely studies in all of biology. Recently, a number of classical heterotrimeric G protein coupled receptors (GPCRs) have been shown to activate the canonical Wnt pathway, culminating in the stabilization of beta-catenin and induction of transcription of genes regulated by the Tcf/Lef family of transactivators. However, mechanisms by which these GPCRs accomplish this differ in key ways, and in some circumstances, the phenotypes produced are novel. Herein, we will examine mechanisms by which classical GPCRs interact with the canonical Wnt pathway, culminating in its activation, and describe the consequences of this activation, focusing on the heart. In the heart, the contractile cells, or cardiomyocytes, are terminally differentiated and virtually exclusively grow by increasing cell size (hypertrophy) rather than cell number, and we will describe how GPCR-mediated activation of the canonical pathway can drive this process.

Animals↗
PubMed2006

The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy.

In cells capable of entering the cell cycle, including cancer cells, beta-catenin has been termed a master switch, driving proliferation over differentiation. However, its role as a transcriptional activator in terminally differentiated cells is relatively unknown. Herein we utilize conditional, cardiac-specific deletion of the beta-catenin gene and cardiac-specific expression of a dominant inhibitory mutant of Lef-1 (Lef-1Delta20), one of the members of the T-cell factor/lymphocyte enhancer factor (Tcf/Lef) family of transcription factors that functions as a coactivator with beta-catenin, to demonstrate that beta-catenin/Tcf/Lef-dependent gene expression regulates both physiologic and pathological growth (hypertrophy) of the heart. Indeed, the profound nature of the growth impairment of the heart in the Lef-1Delta20 mouse, which leads to very early development of heart failure and premature death, suggests beta-catenin/Tcf/Lef targets are dominant regulators of cardiomyocyte growth. Thus, our studies, employing complementary models in vivo, implicate beta-catenin/Tcf/Lef signaling as an essential growth-regulatory pathway in terminally differentiated cells.

Animals↗
PubMed2004

17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling.

Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17beta-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER- and phospho-inositide-3 kinase-Akt-dependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart.

Glycogen synthase kinase (GSK) 3beta is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3beta plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3beta in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca2+] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3beta, acting at the level of the SERCA2 promoter. These studies identify GSK-3beta as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3beta leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.

Animals↗
PubMed2003

Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth.

beta-Catenin is a transcriptional activator that regulates embryonic development as part of the Wnt pathway and also plays a role in tumorigenesis. The mechanisms leading to Wnt-induced stabilization of beta-catenin, which results in its translocation to the nucleus and activation of transcription, have been an area of intense interest. However, it is not clear whether stimuli other than Wnts can lead to important stabilization of beta-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that beta-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which beta-catenin is stabilized is distinctly different from that used by Wnt signaling. Although, as with Wnt signaling, inhibition of glycogen synthase kinase-3 remains central to hypertrophic stimulus-induced stabilization of beta-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the beta-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at beta-catenin. Finally, we demonstrate via adenoviral gene transfer that beta-catenin is both sufficient to induce growth in cardiomyocytes in culture and in vivo and necessary for hypertrophic stimulus-induced growth. Thus, in these terminally differentiated cells, beta-catenin is stabilized by hypertrophic stimuli acting via heterotrimeric G protein-coupled receptors. The stabilization occurs via a unique Wnt-independent mechanism and results in cellular growth.

Animals↗
PubMed2003

Deletion of cytosolic phospholipase A2 promotes striated muscle growth.

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2003

Renal ischemia/reperfusion and ATP depletion/repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1.

BACKGROUND: Cell death and survival pathways are critical determinants of epithelial cell fate after ischemia. Forkhead proteins have been implicated in the regulation of cellular survival. METHODS AND RESULTS: We have found that none of the forkhead family of proteins, FKHR, is phosphorylated after ischemia/reperfusion in the rat kidney. The time course of phosphorylation is similar to the time course of activation of the forkhead protein kinase Akt/protein kinase B (PKB), with maximal phosphorylation at 24 to 48 hours postreperfusion when the process of regeneration peaks. Extracellular signal-regulated kinase (ERK)1/2 activation has also been implicated as prosurvival in the injured kidney. ERK1/2 were phosphorylated in postischemic kidneys at 5, 30, and 90 minutes of reperfusion, with phosphorylation decreased by 24 and 48 hours. Immunocytochemical analysis revealed increased phospho-ERK1/2 in the thick ascending limb and isolated cells of the S3 segment, which have lost apical actin staining. To understand the relationship between forkhead phosphorylation, Akt, and ERK1/2, an in vitro model of injury was employed. After 40 minutes of chemical anoxia followed by dextrose addition for 20 minutes to replete adenosine triphosphate (ATP) levels, FKHR and FKHRL1 are phosphorylated. The levels of phospho-Akt are increased for at least 120 minutes after dextrose addition with a maximum at 20 minutes. Phosphorylation of Akt, FKHR, and FKHRL1 are phosphatidylinositol 3-kinase (PI 3-kinase) dependent since phosphorylation is reduced by the PI 3-kinase inhibitors, wortmannin, or LY294002. Inhibition of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK1/2), the upstream activator of ERK1/2, has no effect on forkhead protein phosphorylation after chemical anoxia/dextrose addition. CONCLUSION: We conclude that PI 3-kinase and Akt are activated after renal ischemia/reperfusion and that Akt phosphorylation leads to phosphorylation of FKHR and FKHRL1, which may affect epithelial cell fate in acute renal failure.

Adenosine Triphosphate↗
PubMed2002

Stretch-activated pathways and left ventricular remodeling.

Stretch of cardiomyocytes in vivo occurs in response to a number of stimuli, including pressure or volume overload, but it is most clearly seen following relatively large, acute myocardial infarctions. It is in this setting that stretch is most clearly related to the pathogenesis of heart failure. Stretch of the remote, noninfacted myocardium leads to the activation of a large number of cellular signal transduction pathways, which sets into motion a series of what are designed to be compensatory responses to the increased wall stress on the surviving myocardium. Herein, we will discuss the cellular pathways activated by cell stretch, which appear to trigger the initial steps in the pathogenesis of ventricular dilatation following myocardial infarction. We will discuss what is known of the "stretch sensors," which convert the mechanical stimulus into molecular signals. I will then introduce the specific cellular signaling pathways activated by stretch and discuss the evidence for their involvement in remodeling. Since many of these pathways will be covered in more detail in specific sections to follow, this will serve as an introduction to stretch-activated signaling. Finally, we will briefly examine later phases of the response, including advanced heart failure. The goal is to identify molecular modulators that might serve as targets for pharmacologic or molecular intervention.

Angiotensin II↗