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W. Robb MacLellan

Danny El-Nachef, Kyohei Oyama, Yun-Yu Wu, Miles Freeman, Yiqiang Zhang, W Robb MacLellan
Mammalian cardiac myocytes (CMs) stop proliferating soon after birth and subsequent heart growth comes from hypertrophy, limiting the adult heart's regenerative potential after injury. The molecular events that mediate CM cell cycle exit are poorly understood. To determine the epigenetic mechanisms limiting CM cycling in adult CMs (ACMs) and whether trimethylation of lysine 9 of histone H3 (H3K9me3), a histone modification associated with repressed chromatin, is required for the silencing of cell cycle genes, we developed a transgenic mouse model where H3K9me3 is specifically removed in CMs by overexpression of histone demethylase, KDM4D...
May 22, 2018: Journal of Molecular and Cellular Cardiology
Kyohei Oyama, Danny El-Nachef, Chen Fang, Hidemi Kajimoto, Jeremy P Brown, Prim B Singh, W Robb MacLellan
BACKGROUND: Heterochromatin, which is formed when tri-methyl lysine 9 of histone H3 (H3K9me3) is bound by heterochromatin 1 proteins (HP1s), plays an important role in differentiation and senescence by silencing cell cycle genes. Cardiac myocytes (CMs) accumulate heterochromatin during differentiation and demethylation of H3K9me3 inhibits cell cycle gene silencing and cell cycle exit in CMs; however, it is unclear if this process is mediated by HP1s. In this study, we created a conditional CM-specific HP1 gamma (HP1γ) knockout (KO) mouse model and tested whether HP1γ is required for cell cycle gene silencing and cardiac growth...
April 17, 2018: Epigenetics & Chromatin
Yiqiang Zhang, Jiang F Zhong, Hongyu Qiu, W Robb MacLellan, Eduardo Marbán, Charles Wang
This corrects the article DOI: 10.1038/srep17686.
October 20, 2017: Scientific Reports
Yiqiang Zhang, Jiang F Zhong, Hongyu Qiu, W Robb MacLellan, Eduardo Marbán, Charles Wang
It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs...
December 14, 2015: Scientific Reports
Yiqiang Zhang, John Mignone, W Robb MacLellan
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear...
October 2015: Physiological Reviews
Nuria Gago-Lopez, Obinna Awaji, Yiqiang Zhang, Christopher Ko, Ali Nsair, David Liem, April Stempien-Otero, W Robb MacLellan
Despite over a decade of intense research, the identity and differentiation potential of human adult cardiac progenitor cells (aCPC) remains controversial. Cardiospheres have been proposed as a means to expand aCPCs in vitro, but the identity of the progenitor cell within these 3D structures is unknown. We show that clones derived from cardiospheres could be subdivided based on expression of thymocyte differentiation antigen 1 (THY-1/CD90) into two distinct populations that exhibit divergent cardiac differentiation potential...
May 6, 2014: Stem Cell Reports
Julie W Creaser, Darlene Rourke, Elizabeth Vandenbogaart, Tamara Chaker, Ali Nsair, Richard Cheng, Gregg Fonarow, Nancy Livingston, Elan Howell, Newman Huie, Arnold S Baas, Mario Deng, Ann Hickey, Richard J Shemin, W Robb MacLellan
BACKGROUND: The use of left ventricular assist devices has grown rapidly in recent years for patients with end-stage heart failure. A significant proportion of patients require both left- and right-sided support with biventricular assist devices (BiVADs) as a bridge to transplantation. Traditionally, these patients have waited in the hospital until they receive a transplant. PURPOSE: The aim of this study was to characterize the clinical course of BiVAD patients discharged to home to await heart transplantation...
July 2015: Journal of Cardiovascular Nursing
Jessica M Gluck, Connor Delman, Jennifer Chyu, W Robb MacLellan, Richard J Shemin, Sepideh Heydarkhan-Hagvall
We examined the effects of the microenvironment on vascular differentiation of murine cardiovascular progenitor cells (CPCs). We isolated CPCs and seeded them in culture exposed to the various extracellular matrix (ECM) proteins in both two-dimensional (2D) and 3D culture systems. To better understand the contribution of the microenvironment to vascular differentiation, we analyzed endothelial and smooth muscle cell differentiation at both day 7 and day 14. We found that laminin and vitronectin enhanced vascular endothelial cell differentiation while fibronectin enhanced vascular smooth muscle cell differentiation...
November 2014: Journal of Biomedical Materials Research. Part B, Applied Biomaterials
Juyong Brian Kim, Susan Hama, Greg Hough, Mohamad Navab, Alan M Fogelman, W Robb Maclellan, Tamara B Horwich, Gregg C Fonarow
Oxidative stress and inflammation are hallmarks of the heart failure (HF) disease state. In the present study, we investigated the inflammatory/anti-inflammatory characteristics of high-density lipoproteins (HDL) in patients with HF. Ninety-six consecutive patients with systolic HF were followed in an advanced HF center, and 21 healthy subjects were recruited. Plasma was tested for HDL inflammatory index (HII) using a monocyte chemotactic activity assay, with HII >1.0 indicating proinflammatory HDL. We found significantly increased inflammatory properties of HDL in patients with HF (median HII 1...
December 1, 2013: American Journal of Cardiology
Kyohei Oyama, Danny El-Nachef, W Robb MacLellan
Although adult cardiac myocytes (CMs) have very little proliferative potential, fetal CMs divide robustly. The mechanisms underlying the post-mitotic state of CMs are poorly understood; however, recently Mahmoud et al. identified a homeodomain transcription factor, Meis1, which controls postnatal CM cell cycle.
August 2013: Cell Research
Preeti Ahuja, Jonathan Wanagat, Zhihua Wang, Yibin Wang, David A Liem, Peipei Ping, Igor A Antoshechkin, Kenneth B Margulies, W Robb Maclellan
BACKGROUND: Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. METHODS AND RESULTS: To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts...
May 14, 2013: Circulation
Charles E Murry, Nathan J Palpant, W Robb MacLellan
No abstract text is available yet for this article.
June 11, 2013: Journal of the American College of Cardiology
Patima Sdek, Kyohei Oyama, Ekaterini Angelis, Shing S Chan, Katja Schenke-Layland, W Robb MacLellan
Heterochromatin protein 1 (HP1) is an essential heterochromatin-associated protein typically involved in the epigenetic regulation of gene silencing. However, recent reports have demonstrated that HP1 can also activate gene expression in certain contexts including differentiation. To explore the role of each of the three mammalian HP1 family members (α, β and γ) in skeletal muscle, their expression was individually disrupted in differentiating skeletal myocytes. Among the three isoforms of HP1, HP1α was specifically required for myogenic gene expression in myoblasts only...
2013: PloS One
Ali Nsair, Katja Schenke-Layland, Ben Van Handel, Denis Evseenko, Michael Kahn, Peng Zhao, Joseph Mendelis, Sanaz Heydarkhan, Obina Awaji, Miriam Vottler, Susanne Geist, Jennifer Chyu, Nuria Gago-Lopez, Gay M Crooks, Kathrin Plath, Josh Goldhaber, Hanna K A Mikkola, W Robb MacLellan
BACKGROUND: Cardiovascular progenitor cells (CPCs) have been identified within the developing mouse heart and differentiating pluripotent stem cells by intracellular transcription factors Nkx2.5 and Islet 1 (Isl1). Study of endogenous and induced pluripotent stem cell (iPSC)-derived CPCs has been limited due to the lack of specific cell surface markers to isolate them and conditions for their in vitro expansion that maintain their multipotency. METHODOLOGY/PRINCIPAL FINDINGS: We sought to identify specific cell surface markers that label endogenous embryonic CPCs and validated these markers in iPSC-derived Isl1(+)/Nkx2...
2012: PloS One
James N Weiss, Alain Karma, W Robb MacLellan, Mario Deng, Christoph D Rau, Colin M Rees, Jessica Wang, Nicholas Wisniewski, Eleazar Eskin, Steve Horvath, Zhilin Qu, Yibin Wang, Aldons J Lusis
In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks...
August 3, 2012: Circulation Research
Richard K Cheng, Mario C Deng, Chi-hong Tseng, Richard J Shemin, Bernard M Kubak, W Robb MacLellan
BACKGROUND: Prior studies have identified risk factors for survival in patients with end-stage heart failure (HF) requiring left ventricular assist device (LVAD) support. However, patients with biventricular HF may represent a unique cohort. METHODS: We retrospectively evaluated a consecutive cohort of 113 adult, end-stage HF patients at University of California Los Angeles Medical Center who required BIVAD support between 2000 and 2009. RESULTS: Survival to transplant was 66...
August 2012: Journal of Heart and Lung Transplantation
W Robb MacLellan, Yibin Wang, Aldons J Lusis
Common cardiovascular diseases, such as atherosclerosis and congestive heart failure, are exceptionally complex, involving a multitude of environmental and genetic factors that often show nonlinear interactions as well as being highly dependent on sex, age, and even the maternal environment. Although focused, reductionistic approaches have led to progress in elucidating the pathophysiology of cardiovascular diseases, such approaches are poorly powered to address complex interactions. Over the past decade, technological advances have made it possible to interrogate biological systems on a global level, raising hopes that, in combination with computational approaches, it may be possible to more fully address the complexities of cardiovascular diseases...
March 2012: Nature Reviews. Cardiology
Tamara B Horwich, Holly R Middlekauff, W Robb Maclellan, Gregg C Fonarow
BACKGROUND: Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have been shown to reduce sympathetic nervous system (SNS) activation in experimental heart failure (HF). However, this potential mechanism of action of statins in HF has not been well studied in humans. METHODS AND RESULTS: Twenty-six patients with nonischemic systolic HF (left ventricular ejection fraction [LVEF] ≤35%) were randomized to atorvastatin (10 mg) or placebo for 3 months. Pre- and posttreatment testing included echocardiography, laboratory assays, quality of life (QOL) questionnaires, and peroneal nerve muscle sympathetic nerve activity (MSNA) via microneurography...
November 2011: Journal of Cardiac Failure
Imran N Mungrue, Peng Zhao, Yucheng Yao, Haijin Meng, Christoph Rau, Jocelyn V Havel, Theo G M F Gorgels, Arthur A B Bergen, W Robb MacLellan, Thomas A Drake, Kristina I Boström, Aldons J Lusis
OBJECTIVE: ABCC6 genetic deficiency underlies pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted in Abcc6-deficient mice, including dystrophic cardiac calcification. We tested the role of Abcc6 in response to cardiac ischemia-reperfusion (I/R) injury. METHODS AND RESULTS: To determine the role of Abcc6 in cardioprotection, we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30 minutes) followed by reperfusion (48 hours)...
December 2011: Arteriosclerosis, Thrombosis, and Vascular Biology
Ekaterini Angelis, Peng Zhao, Rui Zhang, Joshua I Goldhaber, W Robb Maclellan
E2Fs are a family of transcription factors that regulate proliferation, differentiation and apoptosis in many cell types. E2F-1 is the prototypical E2F and the family member that has most often been implicated in also mediating apoptosis. To better understand the role of E2F-1 in mediating cardiomyocyte injury we initially analyzed E2F family member expression after ischemia/reperfusion (I/R) in vivo or simulated ischemia in vitro. I/R injury in vivo caused a 3.4-fold increase specifically in E2F-1 protein levels...
December 2011: Journal of Molecular and Cellular Cardiology
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