Bruce AllenUniversité de Montréal | UdeM · Department of Medicine
Bruce Allen
PhD
About
155
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Introduction
Bruce Allen, a Research Professor at the Université de Montréal, works at the Montreal Heart Institute. Current projects are: 1) to determine the role of GPCRs (ETBR, ATRs, beta-ARs) on the nuclear membrane in heart cells and 2) identify the role of regulation, targets, and function of MAP kinase-activated protein kinases 2, 3, and 5 in the heart. Research approaches include cell biology, molecular biology, and physiology.
Additional affiliations
March 2011 - present
October 2010 - present
June 1998 - present
Education
May 1985 - December 1991
October 1982 - May 1985
September 1976 - May 1980
Publications
Publications (155)
Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on...
Key points:
The renin-angiotensin system plays a key role in cardiovascular physiology and its overactivation has been implicated in the pathogenesis of several major cardiovascular diseases. There is growing evidence that angiotensin II (Ang-II) may function as an intracellular peptide to activate intracellular/nuclear receptors and their downstr...
ERK3/MAPK6 activates MAP kinase‐activated protein kinase (MK)‐5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac...
Photoactivatable ligands remain valuable tools to study the spatiotemporal aspects of cellular signaling. However, the synthesis, handling, and biological validation of such compounds remain challenging, especially when dealing with peptides. We report an optimized synthetic strategy, where laborious preparation of dimethoxy-nitrobenzyl-tyrosine bu...
Background: Altering the onset, intensity, or duration of inflammation can impact the recovering heart's structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. Th...
ERK3/MAPK6, an atypical MAPK, activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency alters cardiac fibroblast function. This study was to determine the effect of reduc...
The role of different G protein-coupled receptors (GPCRs) in the cardiovascular system is well understood in cardiomyocytes and vascular smooth muscle cells (VSMCs). In the former, stimulation of Gs-coupled receptors leads to increases in contractility, while stimulation of Gq-coupled receptors modulates cellular survival and hypertrophic responses...
Cardiac diseases are the leading cause of mortality and morbidity worldwide. Mounting evidence suggests that transglutaminases (TGs), tissue TG (TG2) in particular, are involved in numerous molecular responses underlying the pathogenesis of cardiac diseases. The TG family has several intra- and extracellular functions in the human body, including c...
Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hyper...
Drug development was historically started by targeting protein active sites as means to pharmacologically modulate the functional properties of the target. However, with high attrition rates, pharmacologists and medicinal chemists must begin thinking outside the box more earnestly when designing new drugs. Such thinking has created an impetus towar...
Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. Here we took advantage of the extraordinary mitochondrial resilience of hepatic Lrpprc knockout mice to explore this question using native proteomic...
Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in neurons, and its release and signaling mechanisms have been extensively studied in the central nervous system. Large quantities of BDNF have been reported in circulation, essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons....
Over the last decade, the urotensinergic system, composed of one G protein-coupled receptor and two endogenous ligands, has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases. Indeed, this system is associated with various biomarkers of cardiovascular dysfunctions and is involved in changes...
Cardiac fibroblasts play a critical role in extracellular matrix homeostasis, wound healing, and cardiac interstitial fibrosis: the latter being a pathophysiological response to a chronic increase in afterload. Using a standard protocol to isolate cardiac fibroblasts and maintain them in their quiescent phenotype in vitro will enable a better under...
Background
Mitogen‐activated protein kinase–activated protein kinase‐2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2‐null (MK2 −/− ) mice.
Methods and Results
Survival curves for male MK2 +/+ and MK2 −/− mice did not differ (Mantel‐Cox test, P =0.580). At 12 weeks of age, MK2 −/...
Peptidylarginine deiminase (PAD) family members have a vital role in maintaining the stability of the extra-cellular matrix (ECM) during remodelling in several heart diseases. PAD-mediated deamination, or citrullination, has been studied in different physiological and pathological conditions in the body. However, the role of PAD isoforms has not be...
Over the last decade, the urotensinergic system has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases and also cancer. Significant investment toward the development of clinically relevant UT ligands for therapeutic intervention has been made but have met little to no success to date. The U...
Cardiac hypertrophy, a common consequence of cardiopathologies such as hypertension and myocardial infarcts, involves formation of excessive interstitial fibrosis, which may impair cardiac function. Fibroblasts are the primary source of extracellular matrix protein. Extracellular-regulated kinase 4 (ERK4) is an atypical mitogen-activated protein ki...
MAP kinase-activated protein kinase-5 (MK5) is a protein serine/threonine kinase involved in fibroblast function. MK5 is activated by phosphorylation at threonine-182 (Thr182): p38α/β, ERK3, and ERK4 have been implicated. We examined the phosphorylation of MK5 in adult cardiac ventricular fibroblasts. In serum-starved cardiac myofibroblasts (fibrob...
MAP kinase-activated protein kinase-5 (MK5) plays an important role in cardiac fibroblast function. Although p38 MAPK and atypical MAPKs and ERK3 and ERK4 have been identified as activators of MK5, the kinases that activate MK5 remain controversial. Here we examined the expression, subcellular distribution, and regulation of MK5 in cardiac ventricu...
Cardiomyocyte migration represents a requisite event of cardiogenesis and the regenerative response of the injured adult zebrafish and neonatal rodent heart. The present study tested the hypothesis that the appearance of the intermediate filament protein nestin in neonatal rat ventricular cardiomyocytes (NNVMs) was associated in part with the acqui...
Background
MAP kinase‐activated protein kinase‐5 (MK5) is a protein serine/threonine kinase identified as a putative substrate of both p38α/β MAPKs and atypical MAPKs ERK3 and ERK4. MK5 mRNA is detected in adult cardiac ventricular fibroblasts and myocytes whereas MK5 immunoreactivity is detected in fibroblasts but not myocytes.Little is known abou...
MAP kinase-activated protein kinase-2 (MK2) is protein serine/threonine kinase activated by p38α/β. Herein we examined the cardiac phenotype of pan MK2-null (MK2 −/− ) mice. Survival curves for male MK2 +/+ and MK2 −/− mice did not differ (Mantel-Cox test, P = 0.580). At 12-weeks of age, MK2 −/− mice exhibited normal systolic function along with si...
Follicle growth and granulosa cell health are dependent on the secretion of estradiol from granulosa cells. Estradiol is synthesized from androgen precursor by cytochrome P450 aromatase (CYP19A1), and in cattle CYP19A1 messenger RNA has a short half‐life but a long (3.5 kb) 3′‐untranslated region (3′UTR), suggesting that posttranscriptional regulat...
Elevated reactive oxygen species (ROS) production plays an important role in the pathogenesis of several diseases, including cardiac hypertrophy. While the regulation of diverse sources of ROS is well characterized in the heart, the redox-sensitive targets that contribute to redox signaling remain largely undefined. We now report that protein tyros...
Heart diseases are a major cause of morbidity and mortality world-wide. Lysyl oxidase (LOX) and related LOX-like (LOXL) isoforms play a vital role in remodelling the extracellular matrix (ECM). The LOX family controls ECM formation by cross-linking collagen and elastin chains. LOX/LOXL proteins are copper-dependent amine oxidases that catalyse the...
MK5 is a protein serine/threonine kinase activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. Although little is known of the physiological role of MK5 in the heart, both hypertrophic growth and the increase in collagen 1-α1 mRNA induced by increased afterload are attenuated in hearts of MK5 haploinsufficient (MK5+/-) mice. MK5 transcripts a...
Background and objectives
MAP kinase‐activated protein kinase‐5 (MK5), a protein serine/threonine kinase identified as a substrate for p38α/β, ERK3, and ERK4 MAPKs, is expressed in the heart. However, the interacting partners and physiological function of MK5 are just beginning to be understood. Both MK5 and ERK3 haploinsufficiency attenuates the i...
MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts and MK5-haplodeficiency attenuates the increase in collagen 1-a1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myoc...
Background and objectives
Immunoreactivity for MAP kinase‐activated protein kinase‐5 (MK5), a protein serine/threonine kinase, is detected in cardiac ventricular fibroblasts but not myocytes. p38 and ERK3/4 MAP kinases are activators of MK5. However, the regulation of MK5 remains controversial and its physiological functions are poorly understood....
While it is widely recognized that inflammation plays a critical role in the development and pathology of heart failure, very little is known about the involvement of one of the most abundant immune cell in the blood, a primary immune response cell, the neutrophil. This review summarizes the current literature on the role of subclinical inflammatio...
Hepatic low-density lipoprotein receptor (LDLR) is the primary conduit for the clearance of plasma LDL-cholesterol and increasing its expression represents a central goal for treating cardiovascular disease. However, LDLR mRNA is unstable and undergoes rapid turnover mainly due to the three AU-rich elements (ARE) in its proximal 3'-untranslated reg...
MAP kinase-activated protein kinases (MKs), protein serine/threonine kinases downstream of the MAPKs, regulate a number of biological functions. MK5 was initially identified as a substrate for p38 MAPK but subsequent studies revealed that MK5 activity is regulated by atypical MAPKs ERK3 and ERK4. However, the roles of these MAPKs in activating MK5...
There is significant evidence that internal pools of GPCRs exist and may be affected by both endogenous signaling molecules and hydrophobic pharmaceutical ligands, once assumed to only affect cell surface versions of these receptors. Here, we discuss evidence that the biology of nuclear GPCRs in particular is complex, rich and highly interactive wi...
MAP kinase-activated protein kinase-5 (MK5), a protein serine/threonine kinase expressed in the heart, has been identified as a substrate for p38α/β and ERK3/4 MAPKs. However, the interacting partners and physiological function of MK5 are just beginning to be understood. This study examined the role of MK5 in murine cardiac ventricular fibroblasts....
Voltage-gated L-type CaV1.2 channels in cardiomyocytes exist as heteromeric complexes with the pore-forming CaVα1, CaVβ, and CaVα2δ1 subunits. The full complement of subunits is required to reconstitute the native-like properties of L-type Ca(2+) currents but the molecular determinants responsible for the formation of the heteromeric complex are st...
Background Cardiac fibroblasts play important functional and pathophysiological roles. Intracellular (“intracrine”) angiotensin‐II (Ang‐II) signaling regulates intercellular communication, excitability, and gene expression in cardiomyocytes; however, the existence and role of intracrine Ang‐II signaling in cardiac fibroblasts is unstudied. Here, we...
Figure S1. Isolation of nuclei from atrial fibroblasts. Images show isolated nuclei in phase contrast (A) or labeled with either the DNA stain DRAQ5 (B) or Alexa Fluor 594‐conjugated transferrin, a marker of cell surface membranes (C). The histogram (D) shows the total nucleic acid content of the cytosolic and the nuclear fractions. Mean±SEM, ***P<...
Fibroblasts represent the principal source of collagen in the heart. Increased interstitial fibrosis is a result of changes in both the deposition and breakdown of intracellular matrix proteins, including collagen. We have shown previously that the ability of chronic pressure overload to increase cardiac ventricular Col1α1 mRNA levels and collagen...
Abstract: Cardiac fibroblasts are the most predominant cell type in the heart. They play a critical role in post-infarction cardiac repair following myocyte loss and are implicated in the pathogenesis of cardiac remodelling. MAP kinase-activated protein kinase-5 (MK5) is highly expressed in the heart but its physiological role is just beginning to...
Abstract: Type B endothelin receptors (ETB) are located in the nuclear envelope of adult ventricular cardiomyocytes (ACVMs). Activation of nuclear ETB induces a transient increase in nuclear calcium, activates NO production, and inhibits transcription initiation. In both ACVMs and endothelial cells, endocytosed rhodamine-endothelin colocalized with...
First characterized in neuronal tissues, the multifunctional Calcium/Calmodulin-dependent protein kinase II (CaMKII) is a key signaling component in several mammalian biological systems. Its unique capacity to integrate various Ca(2+) signals into different specific outcomes is a precious asset to excitable and non-excitable cells. Numerous studies...
Background and objectives
MAP kinase-activated protein kinase-5 (MK5, PRAK) was originally discovered as target of p38 MAPK. Subsequent studies suggested that MK5 activity is regulated by atypical MAPKs ERK3 and 4 (Extracellular Signal-regulated Kinase 3 and 4). The physiological role of MK5, in addition to the mechanisms regulating its activity an...
Heart disease remains a major complication of diabetes and identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38MAPK downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2 null (MK2(-/-)) mice using repeated inje...
Protein kinases are potential therapeutic targets for heart failure, but most studies of cardiac protein kinases derive from other systems, an approach that fails to account for specific kinases expressed in the heart and the contractile cardiomyocytes. We aimed to define the cardiomyocyte kinome (i.e. the protein kinases expressed in cardiomyocyte...
In addition to cell surface membranes, numerous G protein-coupled receptors (GPCRs) are located on intracellular membranes including the nuclear envelope. Although the role of numerous GPCRs at the cell surface has been well characterized, the physiological function of these same receptors located on intracellular membranes remains to be determined...
: G protein-coupled receptors (GPCRs) play key physiological roles and represent a significant target for drug development. However, historically, drugs were developed with the understanding that GPCRs as a therapeutic target exist solely on cell surface membranes. More recently, GPCRs have been detected on intracellular membranes, including the nu...
The measurement of changes in the transcriptome is a common end point for various pathologic and pharmacologic studies. In recent years, with the discovery of a host of potential pharmacologic targets located directly on the nuclear membrane, the need to assess their potential control over the transcriptome has arisen. Here we present techniques fo...
Intracrine signaling refers to the activation of receptors located within the cell and many intracrine receptors have been localized to the nuclear membrane. The presence and function of nuclear receptors have been studied in isolated nuclei. Much less information is available concerning the function of these receptors within the context of intact...
The nuclear envelope encloses the genome as well as the molecular machinery responsible for both the replication and transcription of DNA as well as the maturation of nascent RNA. Recent studies ascribe a growing number of functions to the nuclear membrane, in addition to sequestering the DNA, through receptors and their effectors, ion channels, as...
Nuclear G-Protein Coupled Receptors: Methods and Protocols is a compilation of a number of conceptual and methodological aspects important for the validation and characterization of intacrine signaling systems. To date, the best-characterized intracrine signaling system is that of angiotensin II (Ang II), covered in depth in various chapters. Metho...
Angiopoietin-like protein 2 (Angptl2) is a secreted glycoprotein that has been implicated in angiogenesis, inflammation and atherosclerosis as well as enhancing the survival of human hematopoietic stem cells. Glycosylation of Angptl2 is required for biological activity and studies of angiopoietin-like protein 2 have been hindered by the lack of a s...
At the cell surface, βARs and endothelin receptors can regulate nitric oxide (NO) production. β-adrenergic receptors (βARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G pr...
Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (ECs) from patients with coronary artery disease (CAD). Whether angptl2 contributes to atherogenesis is unknown. We tested the hypothesis that angptl2 promotes inflammation and leukocyte adhesion onto ECs, thereby accelerating atherogenesis in preatheros...
RATIONALE AND GOAL: Glutamine, the most abundant amino acid in plasma, has attracted considerable interest for its cardioprotective properties. The primary effect of glutamine in the heart is commonly believed to be mediated via its anaplerotic metabolism to citric acid cycle (CAC) intermediates; however, there is little direct evidence to support...
Chronic hemodynamic overload results in left ventricular hypertrophy, fibroblast proliferation, and interstitial fibrosis. The small heat shock protein hsp27 has been shown to be cardioprotective and this requires a phosphorylatable form of this protein. To further understand the regulation of hsp27 in heart in response to stress, we investigated t...
Angiopoietin like‐2 (Angptl2), which circulating levels are increased in patients with coronary artery disease, could contribute to chronic inflammation. We hypothesized that the pro‐inflammatory effect of Angptl2 contributes to atherogenesis by stimulating leukocyte adhesion in atherosclerotic mice (LDLr −/− ; hApoB 100 +/+ , ATX).
In C57Bl/6 cont...
Both β‐adrenergic receptors (β‐ARs) and endothelin receptors (ETRs) have been shown to be present on nuclear membranes in adult cardiac ventricular myocytes. These nuclear‐localized receptors are functional with respect to ligand binding and effector activation. Furthermore, isoproterenol (ISO) increases transcription initiation in isolated nuclei...
G protein-coupled receptors (GPCRs) play key physiological roles in numerous tissues, including the heart, and their dysfunction influences a wide range of cardiovascular diseases. Recently, the notion of nuclear localization and action of GPCRs has become more widely accepted. Nuclear-localized receptors may regulate distinct signalling pathways,...
p38 mitogen-activated protein kinases (MAPKs) regulate a broad range of cellular activities but have been implicated in the pathogenesis of cardiovascular diseases. The mechanisms whereby p38 exerts divergent effects are unknown. Current p38 inhibitors both produce serious side effects and loose efficacy with chronic use. Hence, a better understand...
In recent years, we have come to appreciate the complexity of G protein-coupled receptor signaling in general and β-adrenergic receptor (β-AR) signaling in particular. Starting originally from three β-AR subtypes expressed in cardiomyocytes with relatively simple, linear signaling cascades, it is now clear that there are large receptor-based networ...
Transgenic mice that overexpress human type 1 angiotensin II receptor (AT(1)R) in the heart develop cardiac hypertrophy. Previously, we have shown that in 6-mo AT(1)R mice, which exhibit significant cardiac remodeling, fractional shortening is decreased. However, it is not clear whether altered contractility is attributable to AT(1)R overexpression...
CD36, a multifunctional protein, is involved in cardiac long chain fatty acid (LCFA) metabolism and in the etiology of heart diseases, yet the functional impact of Cd36 gene variants remains unclear. In 7-week-old spontaneously hypertensive rats (SHR), which, like humans, carry numerous mutations in Cd36, we tested the hypothesis that their restric...
Adiponectin is an adipokine whose plasma levels are inversely correlated to metabolic syndrome components. Adiponectin protects against atherosclerosis and decreases risks in myocardial infarction. Endothelial progenitor cells (EPCs) are a heterogeneous population of circulating cells involved in vascular repair and neovascularization. EPCs number...
Both β(1)- and β(3)-adrenergic receptors (β(1)ARs and β(3)ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured usin...
There is a growing population of adults with repaired cyanotic congenital heart disease. These patients have increased risk of impaired cardiac health and premature death. We hypothesized that hypoxia in early life before surgical intervention causes lasting changes in left ventricular structure and function with physiological implications in later...
p38 mitogen-activated protein kinases (MAPKs) are serine/threonine specific protein kinases that respond to cellular stress and regulate a broad range of cellular activities. There are four major isoforms of p38 MAPK: alpha, beta, gamma, and delta. To date, the prominent isoform in heart has been thought to be p38alpha. We examined the expression o...
p38 MAP kinase (MAPK) isoforms alpha, beta, and gamma, are expressed in the heart. p38alpha appears pro-apoptotic whereas p38beta is pro-hypertrophic. The mechanisms mediating these divergent effects are unknown; hence elucidating the downstream signaling of p38 should further our understanding. Downstream effectors include MAPK-activated protein k...