Abstract
Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well-suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein alpha (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18-kDa (TSPO) and the norepinephrine transporter (NET), respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.
Authors
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John W. Babich, Annarita Di Lorenzo, James M. Kelly
Abstract
Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.
Authors
Maria Laskou, Sofie Delbare, Michael Gildea, Ada Weinstock, Vitor De Moura Virginio, Maxwell La Forest, Franziska Krautter, Casey Donahoe, Letizia Amadori, Natalia Eberhardt, Tessa J. Barrett, Chiara Giannarelli, Jeffrey S. Berger, Edward A. Fisher
Abstract
The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, comprises distinct pathways orchestrated by conserved molecular sensors. Although several of these components have been suggested to protect cardiomyocytes from ischemic injury, their precise functions and mechanisms remain elusive. In this study, we observed a marked increase in glucose-regulated protein 94 (GRP94) expression at the border zone of cardiac infarct in a mouse model. GRP94 overexpression ameliorated post-infarction myocardial damage and reduced infarct size. Conversely, GRP94 deficiency exacerbated myocardial dysfunction and infarct size. Mechanistically, GRP94 alleviated hypoxia-induced mitochondrial fragmentation, whereas its depletion exacerbated this fragmentation. Molecular investigations revealed that GRP94 specifically facilitated the cleavage of Opa1 into L-Opa1, but not S-Opa1. The study further elucidated that under hypoxic conditions, the binding shift of Yy1 from lncRNA Oip5os1 to AI662270 promoted Yy1’s binding on the GRP94 promoter, thereby enhancing GRP94 expression. AI662270 attenuated mitochondrial over-fragmentation and ischemic injury after myocardial infarction similarly to GRP94. Moreover, coimmunoprecipitation coupled with LC-MS/MS identified the interaction of GRP94 with Anxa2, which regulates Akt1 signaling to maintain L-Opa1 levels. Overall, these findings unveiled what we believe is a novel role for the AI662270/GRP94 axis in linking ER stress to mitochondrial dynamics regulation, proposing new therapeutic avenues for managing cardiovascular conditions through ER stress modulation.
Authors
Suling Ding, Wen Liu, Zhiwei Zhang, Xiyang Yang, Dili Sun, Jianfu Zhu, Xiaowei Zhu, Shijun Wang, Mengshi Xie, Hongyu Shi, Junbo Ge, Xiangdong Yang
Abstract
Atrial fibrillation (AF) is a prevalent arrhythmia with known detriments such as heart failure, stroke, and cognitive decline even in patients without prior stroke. The mechanisms by which AF leads to cognitive dysfunction are yet unknown and there is a lack of animal models to study this disease process. We previously developed a murine model of spontaneous and prolonged episodes of AF, a double transgenic mouse model with cardiac specific expression of a gain-of-function mutant voltage-gated sodium channel (DTG-AF mice). Herein, we show for the first time a murine model of AF without any cerebral infarcts exhibiting cognitive dysfunction, including impaired visual learning and cognitive flexibility on touchscreen testing. Mesenteric resistance arterial function of DTG-AF mice showed significant loss of myogenic tone, increased wall thickness and distensibility, and mitochondrial dysfunction. Brain pial arteries also showed increased wall thickness and mitochondrial enlargement. Furthermore, DTG-AF mice have decreased brain perfusion on laser speckle contrast imaging compared to controls. Cumulatively, these findings demonstrate AF leads to vascular structural and functional alterations necessary for dynamic cerebral autoregulation resulting in increased cerebral stress and cognitive dysfunction. Expression of mitochondrial catalase (mCAT) to reduce mitochondrial reactive oxygen species (ROS) was sufficient to prevent vascular dysfunction due to AF, restore perfusion, and improve cognitive flexibility.
Authors
Pavithran Guttipatti, Ruiping Ji, Najla Saadallah, Uma Mahesh R. Avula, Deniz Z. Sonmez, Albert Fang, Eric Li, Amar D. Desai, Samantha Parsons, Parmanand Dasrat, Christine Sison, Yanping Sun, Chris N. Goulbourne, Steven R. Reiken, Elaine Y. Wan
Abstract
BACKGROUND. Cardiotoxicity is a major complication of anti-cancer therapy (CTx); yet, the impact of CTx on the human microcirculation is not well defined. This study evaluated the impact of CTx on microvascular function in breast cancer patients. METHODS. Endothelial function and angiogenic potential were assessed in arterioles and adipose biopsies obtained from breast cancer patients before, during, and after CTx (longitudinal and cross-sectional) and in healthy arterioles exposed to doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) ex vivo. Conditioned media containing VEGF-B protein was used to test feasibility of a targeted intervention. RESULTS. Patients treated with Dox and/or TZM in vivo developed profound microvascular endothelial dysfunction that persisted for ≥9 months after treatment cessation. Angiogenic potential was reduced during CTx and recovered within one month after cessation. Gene expression related to angiogenesis and inflammation changed over the course of clinical treatment. Isolated adipose arterioles from healthy donors developed endothelial dysfunction when exposed to Dox or TZM ex vivo. In contrast, paclitaxel (PTX), which poses minimal cardiovascular risk, had no impact on vasomotor function. Ex vivo exposure to Dox or PTX suppressed angiogenic potential, whereas TZM had no effect. Treatment with VEGF-B protein preserved endothelial function in healthy arterioles exposed to Dox or TZM ex vivo. CONCLUSION. Breast cancer patients undergoing treatment with Dox and/or TZM develop prolonged microvascular endothelial dysfunction that is recapitulated in healthy arterioles exposed to Dox or TZM ex vivo. Targeted intervention with VEGF-B protects against direct Dox- or TZM-induced vascular toxicity in human arterioles ex vivo. FUNDING. National Institutes of Health grant R01 HL133029, HL173549 (AMB). National Institutes of Health grant T32 HL134643 (JDT, STH). American Heart Association grant SFRN847970 (AMB, DDG). We Care Foundation Grant (AMB, ALK). Medical College of Wisconsin Cardiovascular Center Pre-PPG Grant (AMB). Advancing a Healthier Wisconsin – Redox Biology Grant (AMB). Jenny and Antti Wihuri Foundation (RMK).
Authors
Janée D. Terwoord, Laura E. Norwood Toro, Shelby N. Hader, Stephen T. Hammond, Joseph C. Hockenberry, Jasmine Linn, Ibrahim Y. Vazirabad, Amanda L. Kong, Alison J. Kriegel, Ziqing Liu, Riikka M. Kivelä, Gillian Murtagh, David D. Gutterman, Andreas M. Beyer
Abstract
Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed a sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM (n=16) and nonfailing donor hearts (n=16). High-resolution mass spectrometry-based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1, FBLN1, and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFβ signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.
Authors
Kevin M. Buck, Holden T. Rogers, Zachery R. Gregorich, Morgan W. Mann, Timothy J. Aballo, Zhan Gao, Emily A. Chapman, Andrew J. Perciaccante, Scott J. Price, Ienglam Lei, Paul C. Tang, Ying Ge
Abstract
Genetic diseases such as ion-channelopathies substantially burden human health. Existing treatments are limited and not genotype specific. Here, we report a two-step high-throughput approach to rapidly identify drug candidates for repurposing as genotype-specific therapy. We first screened 1,680 medicines using a new thallium-flux trafficking assay against KV11.1 gene variants causing Long QT Syndrome (LQTS), an ion-channelopathy associated with fatal cardiac arrhythmias. We identify evacetrapib as a suitable drug candidate that improves membrane trafficking and activates channels. We then use deep mutational scanning to prospectively identify all KV11.1 missense variants in a LQTS hotspot region responsive to treatment with evacetrapib. Combining high-throughput drug screens with deep mutational scanning establishes a new paradigm for mutation-specific drug discovery translatable to personalized treatment of patients with rare genetic disorders.
Authors
Christian L. Egly, Alex Shen, Tri Q. Do, Carlos Tellet Cabiya, Paxton A. Ritschel, Suah Woo, Matthew J. Ku, Brian P. Delisle, Brett Kroncke, Bjorn C. Knollmann
Abstract
Fibroblast Growth Factor Receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance and function of the adrenal cortex with a focus on the zona Glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation and transdifferentiation into zona Fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-Catenin-induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both wild-type and β-Catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.
Authors
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
Abstract
Aortic valve stenosis is a progressive and increasingly prevalent disease in older adults, with no approved pharmacologic therapies to prevent or slow its progression. Although genetic risk factors have been identified, the contribution of epigenetic regulation remains poorly understood. Here, we demonstrated that histone deacetylase 3 (HDAC3) maintains aortic valve structure by suppressing mitochondrial biogenesis and preserving extracellular matrix integrity in valvular interstitial fibroblasts. Human stenotic valves displayed elevated acetylation of histone H3 at lysine 27 (H3K27ac) and reduced HDAC3 activity in diseased regions. Mice lacking HDAC3 in aortic valves developed aortic valve stenosis, disrupted collagen organization, increased H3K27ac, and premature mortality. Mechanistically, HDAC3 loss led to activation of nuclear hormone receptor–regulated mitochondrial gene programs, increased oxidative phosphorylation, and reactive oxygen species–induced damage. Treatment with metformin, a mitochondrial complex I inhibitor, restored redox balance, preserved collagen structure, and improved valve function in Hdac3-deficient mice. Supporting these experimental findings, retrospective clinical analysis revealed a significantly lower prevalence and slower progression of aortic valve stenosis in patients treated with metformin. These results uncovered a potentially previously unrecognized role for HDAC3 in coordinating epigenetic and metabolic homeostasis in the aortic valve, suggesting that targeting mitochondrial dysfunction may offer a therapeutic strategy for noncalcific aortic valve disease.
Authors
Timothy J. Cashman, Sherin Saheera, Ashley E. Blau, Edith Mensah Otabil, Nouran Y. Nagy, Thomas D. Samenuk, Timothy P. Fitzgibbons, David D. McManus, Chinmay M. Trivedi
Abstract
Cardiac hypertrophy is a common adaptation to cardiovascular stress and often a prelude to heart failure. We examined how S-palmitoylation of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), impacts cardiomyocyte stress signaling. Mutation of the cysteine-178 palmitoylation site impaired activation of Rac1 when overexpressed in cardiomyocytes. Cardiomyocyte-specific Rac1 conditional knock-in (Rac1cKI) mice expressing a Rac1C178S mutant protein exhibit normal cardiac structure-function but develop more severe cardiac hypertrophy in response to angiotensin-II (AngII) infusion, cardiomyocyte-specific overexpression of AngII type-I receptor (AT1R), and cardiac pressure overload. Moreover, pressure overload and AT1R overexpression evoked cardiac failure phenotypes in Rac1cKI mice not observed in controls. Mechanistically, Rac1cKI hearts and cardiomyocytes genetically-resistant to Rac1 S-palmitoylation have a profound increase in protein kinase A (PKA) substrate phosphorylation in response to acute β-adrenergic stimulation, as do Rac1cKI hearts subjected to chronic AngII treatment, AT1R overexpression, or pressure overload that correlates with more advanced heart failure phenotypes. This is not associated with increased PKA enzymatic activity, suggesting potential deficits in phosphatase activity at PKA-regulated phospho-sites. Taken together, this study suggests Rac1 S-palmitoylation dampens adrenergic drive and PKA-dependent modulation of the phospho-proteome in response to cardiovascular stress, revealing essential functions for S-acylated Rac1 in cardiac adaptation.
Authors
James P. Teuber, Rachel E. Scissors, Arasakumar Subramani, Nageswara Madamanchi, Matthew J. Brody
No posts were found with this tag.
