Carla Weinheimer

Washington University in St. Louis

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Attila Kovács

Semmelweis University

David M. Ornitz

Washington University in St. Louis

Stacey L. House

Washington University in St. Louis

Attila Kovács

Washington University in St. Louis

Abhinav Diwan

Washington University in St. Louis

Ali Javaheri

Washington University in St. Louis

Babak Razani

Washington University in St. Louis

Anthony J. Muslin

Sanofi (France)

Andrea Ballabio

Federico II University Hospital

Geetika Bajpai

Carilion Clinic

Cooperative Institutions

Washington University in St. Louis

Cardiovascular Research Center

University of Pennsylvania

Massachusetts General Hospital

John Cochran VA Medical Center

Barnes-Jewish Hospital

University of Missouri–St. Louis

Hope Center for Neurological Disorders

Saint Louis University

Jewish Hospital

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Endogenous fibroblast growth factor 2 is cardioprotective in an in vivo, closed-chest, murine model of regional cardiac ischemia-reperfusion injury

Stacey L. House Carla Weinheimer Attila Kovács David M. Ornitz

Cardiac ischemia

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Abstract 14114: Role of Toxic Protein Sequestration by Aggregates in Cardiac Myocytes in Ischemic Cardiomyopathy

Circulation (2021)

Moydul Islam David R. Rawnsley Xiucui Ma Layla Foroughi Chen Zhao

Introduction: Proteotoxic aggregation causes cardiomyopathy (CMP) associated with rare genetic mutations. The role of protein aggregates in ischemic cardiomyopathy is unclear. Hypothesis: Cardiac myocyte protein aggregation is deleterious in cardiomyopathy. Methods: Human (ischemic) and murine (ischemic and proteotoxic) CMP models were profiled by immunohistochemistry (IHC) and proteomic characterization of the detergent-insoluble fraction. Aggregates were evaluated by immunocytochemistry in p62 deficient neonatal mouse cardiac myocytes (NMCMs) with adenoviral transduction of mutant alpha-B crystallin (CRYABR120G). Mice with cardiac myocyte selective p62 deficiency (p62ckO) were generated and characterized (echocardiography, myocardial structure, autophagic flux, mitophagy, and biochemical analyses). p62cKO and floxed controls were subjected to closed-chest ischemia (90 minutes) or sham followed by reperfusion (IR) and evaluated 4 weeks later. Cardiac selective (AAV9-cTnT) reconstitution of p62, its aggregation-deficient K7R mutant or GFP, was performed. Wild-type mice transduced with a fungal disaggregase (AAV9-Hsp104 or control) were modeled for IR as above. Results: Protein aggregation increases in ischemic CMP, but not controls, with increased insoluble CRYAB with phosphorylation at serine 59 (pS59CRYAB). p62-deficient NMCMs are unable to form aggregates following CRYABR120G transduction, indicating the necessity of p62 in protein aggregation. p62cKO mice show preserved baseline cardiac structure/function, without significantly decreased mitophagy or autophagic flux. Compared to controls, p62cKO mice (post-IR) show infarct expansion and impaired LV remodeling at 4 weeks, associated with decreased sequestration of pS59CRYAB in insoluble fraction. Reconstitution with AAV9 p62, but not aggregation-deficient K7R, shows partial functional rescue after IR. Finally, disruption of protein aggregation by AAV9 Hsp104 (but not controls) results in decreased sequestration of pS59CRYAB, and decreased function post-IR. Conclusions: Contrary to the hypothesis, preventing or disrupting protein aggregation, associated with decreased pS59CRYAB sequestration, is maladaptive in ischemic cardiomyopathy.

Ischemic Cardiomyopathy

10.1161/circ.144.suppl_1.14114

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Cardioprotection by endogenous fibroblast growth factor 2 in cardiac ischemia-reperfusion injury in vivo

Stacey L. House Carla Weinheimer Attila Kovács David M. Ornitz

Cardioprotection

Cardiac ischemia

Myocardial Reperfusion Injury

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Human Cord Blood Progenitors with High Aldehyde Dehydrogenase Activity Improve Vascular Density in a Model of Acute Myocardial Infarction

Blood (2008)

Claus S. Søndergaard David A. Hess Dustin J. Maxwell Ivana Rosová Carla Weinheimer

Homing (biology)

10.1182/blood.v112.11.2895.2895

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The 14-3-3τ Phosphoserine-Binding Protein Is Required for Cardiomyocyte Survival

Molecular and Cellular Biology (2006)

Jeffrey M.C. Lau Xiaohua Jin Jie Ren Joan Avery Brian J. DeBosch

14-3-3 family members are intracellular dimeric phosphoserine-binding proteins that regulate signal transduction, cell cycle, apoptotic, and metabolic cascades. Previous work with global 14-3-3 protein inhibitors suggested that these proteins play a critical role in antagonizing apoptotic cell death in response to provocative stimuli. To determine the specific role of one family member in apoptosis, mice were generated with targeted disruption of the 14-3-3tau gene. 14-3-3tau(-/-) mice did not survive embryonic development, but haploinsufficient mice appeared normal at birth and were fertile. Cultured adult cardiomyocytes derived from 14-3-3tau(+/-) mice were sensitized to apoptosis in response to hydrogen peroxide or UV irradiation. 14-3-3tau(+/-) mice were intolerant of experimental myocardial infarction and developed pathological ventricular remodeling with increased cardiomyocyte apoptosis. ASK1, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase (MAPK) activation was increased, but extracellular signal-regulated kinase MAPK activation was reduced, in 14-3-3tau(+/-) cardiac tissue. Inhibition of p38 MAPK increased survival in 14-3-3tau(+/-) mice subjected to myocardial infarction. These results demonstrate that 14-3-3tau plays a critical antiapoptotic function in cardiomyocytes and that therapeutic agents that increase 14-3-3tau activity may be beneficial to patients with myocardial infarction.

Phosphoserine

10.1128/mcb.01369-06

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Fibroblast growth factor 2 affects vascular remodeling after acute myocardial infarction

Stacey L. House Thomas Belanger Carla Weinheimer David M. Ornitz

Ventricular remodeling

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Abstract 15205: Enhancing Effective Drug Delivery in Cardiac Ischemia Reperfusion Injury With Semipermeable Nanoparticles

Circulation (2018)

Samuel A. Wickline Katherine M. James Jawad Fazal Carla Weinheimer Hua Pan

Introduction: Prevention of cardiac ischemia-reperfusion injury (IRI) can be thwarted by microvascular damage that prevents sufficient access of therapeutic agents. We sought to define the state of...

Semipermeable membrane

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Abstract 793: Macrophage Transcription Factor EB Attenuates Left Ventricular Remodeling Via Lysosomal Lipolysis

Circulation Research (2019)

Ali Javaheri Geetika Bajpai Antonino Picataggi Smrithi Mani Layla Foroughi

Background: Autophagy, lipid metabolism, and inflammation are interrelated cellular processes that implicate lysosomes in human disease. After ischemia reperfusion (IR) injury, inflammasome activation and interleukin 1-beta (IL1-beta) secretion promote heart failure progression. Whether macrophage autophagy and lysosomal biogenesis can attenuate post-IR remodeling and inflammation is unknown. We hypothesized that macrophages exhibit lysosome dysfunction and autophagic impairment after IR injury, and that augmentation of macrophage lysosomal biogenesis via macrophage-specific overexpression of transcription factor EB (Mf-TFEB), a master regulator of autophagy and lysosomal biogenesis, would attenuate myocardial remodeling and inflammation in ischemic cardiomyopathy. Methods and Results: In mice subject to IR injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal and autophagic impairment. To ameliorate post-IR macrophage lysosomal injury, we expressed Mf-TFEB in a closed-chest IR murine model using a tamoxifen-inducible CX3CR1erCre and TFEB overexpression cassette bearing a Cre-excisable STOP codon. Compared to Cre-only controls, Mf-TFEB mice had significantly increased left ventricular (LV) ejection fraction 28-days post-IR (40% relative increase, p=0.002, n=15-17 per group), decreased abundance of pro-inflammatory macrophages, and reduced levels of IL1-beta in myocardial tissue. Surprisingly, neither inflammasome suppression nor TFEB-mediated attenuation of post-IR remodeling required intact macro-autophagy as evidenced by Mf-TFEB-mediated rescue of post-IR LV dysfunction in mice with concomitant inducible ATG5 ablation. RNA sequencing of flow-sorted macrophages from post-IR mice identified lysosomal acid lipase amongst other lipases regulated by TFEB. Mechanistically, pharmacologic inhibition of lysosomal acid lipase specifically abrogated the in vivo effects of TFEB on post-IR remodeling. Conclusions: Our findings suggest that macrophage TFEB regulates lysosomal lipolysis to attenuate inflammasome activity and protect against post-IR LV dysfunction, suggesting an alternative paradigm for how lysosome function may impact acute inflammation in vivo.

TFEB

10.1161/res.125.suppl_1.793

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Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury

AJP Heart and Circulatory Physiology (2016)

Stacey L. House Angela Maria Spínola-Castro Traian S. Lupu Carla Weinheimer Craig R. Smith

Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice). Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.

10.1152/ajpheart.00758.2015

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ENDOTHELIAL FIBROBLAST GROWTH FACTORS PROTECT AGAINST GROUP 3 HYPOXIA INDUCED PULMONARY HYPERTENSION

Journal of the American College of Cardiology (2019)

Kel Vin Woo Philip Levy Carla Weinheimer Attila Kovács Gautam K. Singh

Hypoxia

Bronchopulmonary Dysplasia

FGF21

10.1016/s0735-1097(19)33673-3

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Citations (4)