Article
Chemistry, Multidisciplinary
Ajit Magadum, Neha Singh, Ann Anu Kurian, Mohammad Tofael Kabir Sharkar, Nishat Sultana, Elena Chepurko, Keerat Kaur, Magdalena M. Zak, Yoav Hadas, Djamel Lebeche, Susmita Sahoo, Roger Hajjar, Lior Zangi
Summary: Heart failure remains a major issue globally, with cardiac hypertrophy and fibrosis being key factors. The regulator Pip4k2c, associated with mTORC1, plays a role in these processes. Studies show that deleting Pip4k2c does not affect embryonic cardiac development, but leads to increased rates of CH, CF, and sudden death in adult mice. Upregulating Pip4k2c improves heart function, reverses CH and CF, and enhances survival through inhibiting TGF beta 1 via specific pathways. Loss-and-gain-of-function studies identify Pip4k2c as a potential therapeutic target for CF, CH, and HF, utilizing modRNA as an effective gene therapy approach.
Article
Multidisciplinary Sciences
Akito Eguchi, Ryan Coleman, Kenneth Gresham, Erhe Gao, Jessica Ibetti, J. Kurt Chuprun, Walter J. Koch
Summary: Pathological remodeling of the heart in chronic heart failure is linked to structural changes perpetuated by cardiac fibroblasts, with GRK5 playing a key role in regulating fibroblast activation and cardiac fibrosis. GRK5 inhibition shows potential beneficial effects in cardiac disease by preventing fibroblast activation and reducing fibrosis and hypertrophy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Cell Biology
Yusra Zaidi, Eslie G. Aguilar, Miguel Troncoso, Daria Ilatovskaya, Kristine Y. DeLeon-Pennell
Summary: Myocardial infarction (MI) results in pathological changes in the left ventricle's extracellular matrix, which can cause cardiac stiffness and affect systolic and diastolic function. The signals released from necrotic tissue initiate an immune cascade and lead to inflammatory response and reparative fibrosis, with immune cells playing key roles in balancing pro-fibrotic and anti-fibrotic responses. This review explores how molecular signals between fibroblasts and immune cells regulate fibrosis post-MI, and discusses emerging pharmacological targets and therapies for inflammation and cardiac fibrosis associated with MI.
CELLULAR SIGNALLING
(2021)
Article
Pharmacology & Pharmacy
Prachi Umbarkar, Anand P. Singh, Sultan Tousif, Qinkun Zhang, Palaniappan Sethu, Hind Lal
Summary: Nintedanib (NTB) is an FDA-approved tyrosine kinase inhibitor for pulmonary fibrosis, and study shows its potential in reducing cardiac fibrosis and improving cardiac function in a murine heart failure model, suggesting its promising application in treating HF patients.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Genetics & Heredity
Yijing Tao, ChengJie Gao, Da Qian, Donglai Cao, Leng Han, Ling Yang
Summary: In this study, fibrosis-related hub genes in HF were identified and 6 of them were demonstrated as potential diagnostic biomarkers for HF.
FRONTIERS IN GENETICS
(2022)
Article
Multidisciplinary Sciences
Jian Huang, Luxin Wang, Yunli Shen, Shengqi Zhang, Yaqun Zhou, Jimin Du, Xiue Ma, Yi Liu, Dandan Liang, Dan Shi, Honghui Ma, Li Li, Qi Zhang, Yi-Han Chen
Summary: The kinase CLK4 regulates cardiac function by phosphorylating NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.
NATURE COMMUNICATIONS
(2022)
Review
Peripheral Vascular Disease
Javier Diez, Javed Butler
Summary: Hypertensive heart disease is a significant cause of heart failure and its prevalence has been increasing despite improvements in hypertension treatment. The prevention of heart failure in patients with hypertensive heart disease is an important unmet medical need. This article proposes a new perspective that focuses on the detection and reversal of histological changes in the hypertensive heart, particularly myocardial interstitial fibrosis.
Article
Cardiac & Cardiovascular Systems
Sebastian Rosch, Karl-Patrik Kresoja, Christian Besler, Karl Fengler, Anne Rebecca Schoeber, Maximilian von Roeder, Christian Luecke, Matthias Gutberlet, Karin Klingel, Holger Thiele, Karl-Philipp Rommel, Philipp Lurz
Summary: In this study, patients with heart failure with preserved ejection fraction (HFpEF) were stratified based on left ventricular ejection fraction (LVEF), resulting in distinct morphologic and pathophysiologic subphenotypes. Patients with LVEF ranging from 50% to 60% demonstrated reduced contractility, impaired ventriculo-arterial coupling, and higher extracellular volume fraction, while patients with LVEF >60% exhibited a hypercontractile state with excessive left ventricular afterload and diminished preload reserve.
Article
Biochemistry & Molecular Biology
Shuai Yuan, Heidi M. Schmidt, Katherine C. Wood, Adam C. Straub
Summary: CoQ is ubiquitously embedded in lipid bilayers of various cellular organelles, playing a crucial role in maintaining mitochondrial function and heart health. Clinical studies have shown promising results for CoQ supplementation in treating heart failure.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Review
Pharmacology & Pharmacy
Fabiana Passaro, Carlo Gabriele Tocchetti, Gaia Spinetti, Francesca Paudice, Luigi Ambrosone, Ciro Costagliola, Francesco Cacciatore, Pasquale Abete, Gianluca Testa
Summary: Heart failure is a clinical syndrome caused by cardiac structural and/or functional abnormalities, leading to reduced cardiac output and/or elevated intracardiac pressures. Nanoparticles can be used for targeted drug delivery to identify, prevent, and treat cardiac fibrosis.
ADVANCED DRUG DELIVERY REVIEWS
(2021)
Article
Cardiac & Cardiovascular Systems
Satyam Sarma, Erin Howden, Justin Lawley, Mitchel Samels, Benjamin D. Levine
Summary: Patients with HFpEF have lower peak oxygen consumption and heart rate compared to senior controls, but there were no significant differences in peak heart rate response during static handgrip exercise and metaboreceptor function between the two groups. The key reflex autonomic pathways regulating exercise heart rate responsiveness are intact in HFpEF despite lower peak exercise heart rates.
Article
Immunology
Shangjie Zou, Bee Luan Khoo
Summary: This study aims to subtype heart failure patients based on immune cell fractions and explore their differences in fibrotic mechanisms. Two subtypes of immune cell fractions, pro-inflammatory and pro-remodeling, were identified. A 30-gene biomarker panel (ImmunCard30) was established for diagnosing patient subtypes with high classification performance.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Jin-Ling Huo, Lemin Jiao, Qi An, Xiuying Chen, Yuruo Qi, Bingfei Wei, Yichao Zheng, Xiaojing Shi, Erhe Gao, Hong-Min Liu, Dong Chen, Cong Wang, Wen Zhao
Summary: This study evaluates the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. The findings suggest that myofibroblast-specific LSD1 deletion attenuates transverse aortic constriction-induced cardiac remodeling and improves heart function, highlighting LSD1 as a potential therapeutic target for late-stage heart failure.
CIRCULATION RESEARCH
(2021)
Review
Cardiac & Cardiovascular Systems
Stefan Frantz, Moritz Jens Hundertmark, Jeanette Schulz-Menger, Frank Michael Bengel, Johann Bauersachs
Summary: Most patients survive acute myocardial infarction, but the prevalence of heart failure is increasing, leading to economic strain on healthcare systems. Pathological changes in the heart significantly impact patient outcomes. Risk factors like diabetes, chronic obstructive pulmonary disease, and female sex can distinctively shape the progression towards heart failure.
EUROPEAN HEART JOURNAL
(2022)
Article
Cardiac & Cardiovascular Systems
Walter J. Paulus, Michael R. Zile
Summary: According to the comorbidity-inflammation paradigm, comorbidities, especially metabolic ones, are believed to drive the development and severity of heart failure with preserved ejection fraction. Recent evidence includes myocardial infiltration, inducible nitric oxide synthase expression, patient phenogroups, and direct connections between comorbidities, inflammatory biomarkers, and abnormal myocardial structure/function.
CIRCULATION RESEARCH
(2021)
Article
Cardiac & Cardiovascular Systems
Yuxuan Guo, Yangpo Cao, Blake D. Jardin, Xiaoran Zhang, Pingzhu Zhou, Silvia Guatimosim, Junsen Lin, Zhan Chen, Yueyang Zhang, Neil Mazumdar, Fujian Lu, Qing Ma, Yao-Wei Lu, Mingming Zhao, Da-Zhi Wang, Erdan Dong, William T. Pu
Summary: The aim of this study is to investigate the role of RYR2 in cardiomyocyte maturation. The researchers used genetic editing techniques to knockout RYR2 and found that its depletion led to structural and transcriptional defects in cardiomyocytes, along with activation of ER stress pathways. The defects in RYR2-depleted cardiomyocytes were partially rescued by an ER stress alleviator.
CARDIOVASCULAR RESEARCH
(2023)
Article
Multidisciplinary Sciences
Fujian Lu, Qing Ma, Wenjun Xie, Carter L. Liou, Donghui Zhang, Mason E. Sweat, Blake D. Jardin, Francisco J. Naya, Yuxuan Guo, Heping Cheng, William T. Pu
Summary: This study uncovers the role of CMYA5 in organizing and regulating the subcellular structures in cardiomyocytes, highlighting its importance in cardiac development, function, and tolerance to pressure overload.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Danielle Murashige, Jae Woo Jung, Michael D. Neinast, Michael G. Levin, Qingwei Chu, Jonathan P. Lambert, Joanne F. Garbincius, Boa Kim, Atsushi Hoshino, Ingrid Marti-Pamies, Kendra S. McDaid, Swapnil V. Shewale, Emily Flam, Steven Yang, Emilia Roberts, Michael P. Morley, Kenneth C. Bedi, Matthew C. Hyman, David S. Frankel, Kenneth B. Margulies, Richard K. Assoian, John W. Elrod, Cholsoon Jang, Joshua D. Rabinowitz, Zoltan Arany
Summary: Contrary to previous assumptions, activation of branched-chain amino acid (BCAA) oxidation actually increases in heart failure (HF) patients. Activation of cardiac BCAA oxidation does not protect from HF, but systemic activation does. Lowering plasma and cardiac BCAAs also does not confer significant protection. Surprisingly, BCAA catabolism leads to lower blood pressure independently of nitric oxide, suggesting a potential mechanism for cardioprotection in HF.
Article
Cardiac & Cardiovascular Systems
Zhen Li, Huijing Xia, Thomas E. Sharp, Kyle B. LaPenna, Antonia Katsouda, John W. Elrod, Josef Pfeilschifter, Karl-Friedrich Beck, Shi Xu, Ming Xian, Traci T. Goodchild, Andreas Papapetropoulos, David J. Lefer
Summary: This study reveals that endothelial CSE modulates endothelial-mesenchymal transition and improves the severity of pressure-overload-induced heart failure by regulating nitric oxide-related mechanisms. Decreased CSE expression leads to increased endothelial-mesenchymal transition, impaired nitric oxide bioavailability, and worsened cardiac fibrosis, function, and exercise capacity. In contrast, overexpression of CSE in endothelial cells enhances nitric oxide production, reduces endothelial-mesenchymal transition and cardiac fibrosis, and improves cardiac and endothelial function, as well as exercise capacity. These findings highlight the potential therapeutic role of endothelium-derived hydrogen sulfide in treating heart failure with reduced ejection fraction.
CIRCULATION RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Joao Victor Cabral-Costa, Carlos Vicente-Gutierrez, Jesus Agulla, Rebeca Lapresa, John W. Elrod, Angeles Almeida, Juan P. Bolanos, Alicia J. Kowaltowski
Summary: Intracellular Ca2+ concentrations are regulated by plasma membrane transporters, endoplasmic reticulum, and mitochondria. The mitochondrial calcium uniporter complex (MCUc) mediates Ca2+ uptake, while the mitochondrial Na+/Ca2+ exchanger (NCLX) facilitates Ca2+ efflux. The Nclx transcript is highly expressed in astrocytes compared to neurons. Inhibiting NCLX in mouse primary culture astrocytes resulted in altered Ca2+ signaling and increased glycolytic flux. Genetic deletion of NCLX in hippocampal astrocytes improved cognitive performance, while deletion in hippocampal neurons impaired cognition.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Cardiac & Cardiovascular Systems
Yijia Li, Hajime Kubo, Daohai Yu, Yijun Yang, Jaslyn P. Johnson, Deborah M. Eaton, Remus M. Berretta, Michael Foster, Timothy A. McKinsey, Jun Yu, John W. Elrod, Xiongwen Chen, Steven R. Houser
Summary: This study found that three independent pathological stressors (increased Ca2+ influx, high-fat diet, and L-NAME) together produced a profound HFpEF phenotype. The primary mechanisms included CM hypertrophy, increased M2-macrophage population, and myocardial fibrosis. SAHA treatment was shown to prevent the severe HFpEF phenotype. These findings provide important clues for novel therapeutic strategies for HFpEF.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A. Aaronson, John M. Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S. Alnemri, Lucia Altucci, Ivano Amelio, David W. Andrews, Rami Aqeilan, Eli Arama, Eric H. Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A. Barlev, Jiri Bartek, Nicolas G. Bazan, Christoph Becker, Francesca Bernassola, Mathieu J. M. Bertrand, Marco E. Bianchi, Mikhail V. Blagosklonny, J. Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D. Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A. Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H. Chen, Emily H. Cheng, Jerry E. Chipuk, John A. Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R. Cubillos-Ruiz, Peter E. Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M. Dawson, Valina L. Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J. Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J. Dixon, Brian D. Dynlacht, Wafik S. El-Deiry, John W. Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J. Garcia-Saez, Abhishek D. Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R. Green, Lloyd A. Greene, Hinrich Gronemeyer, Georg Haecker, Gyorgy Hajnoczky, J. Marie Hardwick, Ygal Haupt, Sudan He, David M. Heery, Michael O. Hengartner, Claudio Hetz, David A. Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jaeaettelae, Ana Janic, Bertrand Joseph, Philipp J. Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L. Kelly, Oliver Kepp, Adi Kimchi, Richard N. Kitsis, Daniel J. Klionsky, Ruth Kluck, Dmitri Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N. Lavrik, John J. Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A. Lipton, Richard A. Lockshin, Carlos Lopez-Otin, Tom Luedde, Marion MacFarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J. Martin, Jean-Claude Martinou, Pier G. Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A. Miao, Ute M. Moll, Cristina Munoz-Pinedo, Daniel J. Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Nunez, Andrew Oberst, Dimitry Ofengeim, Joseph T. Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M. Penninger, Francesca Pentimalli, David M. Pereira, Shazib Pervaiz, Marcus E. Peter, Paolo Pinton, Giovanni Porta, Jochen H. M. Prehn, Hamsa Puthalakath, Gabriel A. Rabinovich, Krishnaraj Rajalingam, Kodi S. Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M. P. Rodrigues, Barak Rotblat, Carla Rothlin, David C. Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M. Ryan, Kristopher A. Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S. Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R. Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W. G. Tait, Daolin Tang, Nektarios Tavernarakis, Carol M. Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G. Vander Heiden, Jacqueline L. Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia von Karstedt, Anne K. Voss, Karen H. Vousden, Domagoj Vucic, Daniela Vuri, Erwin F. Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E. Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi
Summary: Apoptosis is a regulated cell death process involving caspase family proteases. Inhibiting or delaying apoptosis experimentally through pharmacological and genetic strategies has demonstrated its importance in embryonic development, tissue homeostasis, and the pathogenesis of various human disorders. Defects in apoptotic cell death machinery impair development and promote oncogenesis, while inappropriate activation of apoptosis contributes to cell loss and tissue damage in neurological, cardiovascular, renal, hepatic, infectious, neoplastic, and inflammatory conditions.
CELL DEATH AND DIFFERENTIATION
(2023)
Review
Cardiac & Cardiovascular Systems
Bhairab N. Singh, Dogacan Yucel, Bayardo I. Garay, Elena G. Tolkacheva, Michael Kyba, Rita C. R. Perlingeiro, Jop H. Berlo, Brenda M. Ogle
Summary: During cardiac development and morphogenesis, the differentiation of cardiac progenitor cells into mature cardiomyocytes is regulated by factors that also influence proliferation. Understanding the interaction between proliferation and maturation could enhance the use of human induced pluripotent stem cell-derived cardiomyocytes for modeling adult-level cardiac function in engineered cardiac tissues.
CIRCULATION RESEARCH
(2023)
Editorial Material
Biotechnology & Applied Microbiology
Cheryl L. McDonald, Pankaj Qasba, Daniel G. Anderson, Gang Bao, Richard A. Colvin, Donald B. Kohn, Punam Malik, Michael J. Mitchell, William T. Pu, David J. Rawlings, David A. Williams, Terence R. Flotte
HUMAN GENE THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Suya Wang, Erika Yazawa, Erin M. Keating, Neil Mazumdar, Alexander Hauschild, Qing Ma, Haiyan Wu, Yang Xu, Xu Shi, Douglas Strathdee, Robert E. Gerszten, Michael Schlame, William T. Pu
Summary: Barth syndrome is an X-linked disorder caused by loss-of-function mutations in Tafazzin (TAZ). Genetic modifiers strongly influence the phenotypic expression of Taz inactivation.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Dhanendra Tomar, Manfred Thomas, Joanne F. Garbincius, Devin W. Kolmetzky, Oniel Salik, Pooja Jadiya, Suresh K. Joseph, April C. Carpenter, Gyorgy Hajnoczky, John W. Elrod
Summary: MICU1 is a Ca2+-binding protein that regulates mitochondrial Ca2+ uptake and membrane dynamics independently of matrix Ca2+ content. MICU1 interacts with MICOS components MIC60 and CHCHD2 to form the MICOS complex and is essential for proper mitochondrial architecture and cell death signaling. This system allows distinct Ca2+ signaling in the mitochondrial matrix and intermembrane space to modulate cellular energetics and cell death in a coordinated manner.
Article
Multidisciplinary Sciences
Pooja Jadiya, Henry M. Cohen, Devin W. Kolmetzky, Ashlesha A. Kadam, Dhanendra Tomar, John W. Elrod
Summary: Mitochondrial calcium overload contributes to neurodegenerative disease development and progression. Loss of the mitochondrial sodium/calcium exchanger (NCLX) promotes calcium overload, metabolic derangement, redox stress, and cognitive decline in Alzheimer's disease models. Neuronal deletion of NCLX induces an Alzheimer's disease-like pathology, including memory decline, amyloid deposition, tau pathology, synaptic remodeling, and cell death.
Editorial Material
Cell Biology
Henry M. Cohen, Oniel Salik, John W. Elrod
Summary: Mitochondrial calcium (mCa(2+)) is crucial for neuronal cell function and survival. The regulatory mechanisms controlling mCa(2+) uptake and efflux are important for maintaining cellular homeostasis. The recent discovery by Rozenfeld et al. suggests that inhibition of phosphodiesterase 2 (PDE2) enhances mCa(2+) efflux via increased phosphorylation of the mitochondrial Na+/Ca2+ exchanger (NCLX) by protein kinase A (PKA), leading to improved neuronal survival and cognitive performance.
Editorial Material
Cardiac & Cardiovascular Systems
Michael P. P. Lazaropoulos, John W. W. Elrod
CIRCULATION RESEARCH
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Fernando Souza-Neto, Xavier S. Revelo, Jop H. van Berlo
JACC-BASIC TO TRANSLATIONAL SCIENCE
(2023)