Browsing by Subject "Fibrosis"
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Item Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves(BMC, 2023-03-02) Gu, Dongsheng; Soepriatna, Arvin H.; Zhang, Wenjun; Li, Jun; Zhao, Jenny; Zhang, Xiaoli; Shu, Xianhong; Wang, Yongshi; Landis, Benjamin J.; Goergen, Craig J.; Xie, Jingwu; Pediatrics, School of MedicineBackground: Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models. Results: In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves. Conclusions: Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.Item Acute Effects of Sound Assisted Soft Tissue Mobilization (SASTM) on Lower Extremity Flexibility, Isokinetic and Isometric Strength(2019-07) Beer, Jeffrey Allen; Bahamonde, Rafael E.; Loghmani, M. Terry; Naugle, Keith E.; Streepey, Jefferson W.SASTMTM is a myofascial technique used to mobilize soft tissue and aid in the elongation of soft tissue and create physiological change. The purpose of the study was to determine the acute effects of Sound Assisted Soft Tissue Mobilization (SASTMTM) on lower extremity hamstring strength (isokinetic & isometric) and flexibility. Thirty division III male athletes with limited ROM of ≤ 90o of knee extension with 90o of hip flexion while lying supine consented to volunteer. Each subject was treated and measured through a double-blinded experimental design where the subjects and tester were unaware of the real treatment being administered and measured. The research consisted of 4 visits (familiarization/baseline, and 3 data collection session). Testing sessions were conducted a week after the baseline session, followed by two sessions, 2 days and a week after the 1st session. Three different modalities (SASTMTM, Therapeutic Ultrasound and “The Stick”) were performed on a treatment leg, and the opposite leg served as a control. Data collection consisted of a warm-up on a cycle ergometer followed by one randomly chosen modality on the treatment leg. Data collection was conducted using a Cybex 300-isokinetic device and a digital goniometer. Isokinetic strength testing was performed at 60, 180 and 240o/s. Isometric testing was collected at 45o of knee flexion. Repeated two-way ANOVA’s (3-Treatment x 3-Time) were used for statistical analyses to determine the effects of interventions and the time on strength and flexibility. The statistical analyses resulted in no significant results (p≤.05) for acute effects for either strength or flexibility with respect to time, treatment or treatment and time interactions.Item Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP(MDPI, 2018-08) Ravi, Saranya; Parry, Traci L.; Willis, Monte S.; Lockyer, Pamela; Patterson, Cam; Bain, James R.; Stevens, Robert D.; Ilkayeva, Olga R.; Newgard, Christopher B.; Schisler, Jonathan C.; Pathology and Laboratory Medicine, School of MedicineWe previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP-/-). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP-/- mice with the PPARα agonist called fenofibrate. We found that treating CHIP-/- mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP-/- hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism.Item Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12(American Physiological Society, 2019-02-01) Pan, Zhenwei; Ai, Tomohiko; Chang, Po-Cheng; Liu, Ying; Liu, Jijia; Maruyama, Mitsunori; Homsi, Mohamed; Fishbein, Michael C.; Rubart, Michael; Lin, Shien-Fong; Xiao, Deyong; Chen, Hanying; Chen, Peng-Sheng; Shou, Weinian; Li, Bai-Yan; Medicine, School of MedicineCardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.Item BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways(Elsevier, 2019-12-27) Qu, Xiuxia; Liu, Ying; Cao, Dayan; Chen, Jinghai; Liu, Zhuo; Ji, Hongrui; Chen, Yuwen; Zhang, Wenjun; Zhu, Ping; Xiao, Deyong; Li, Xiaohui; Shou, Weinian; Chen, Hanying; Pediatrics, School of MedicineBone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.Item Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury(American Society for Clinical Investigation, 2019-11-01) Mehrotra, Purvi; Sturek, Michael; Neyra, Javier A.; Basile, David P.; Anatomy and Cell Biology, School of MedicineWe hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10-7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17+ cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1+ cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4+ cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression.Item Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity(American Medical Association, 2023) Buck, Benjamin; Chum, Aaron P.; Patel, Mitkumar; Carter, Rebecca; Nawaz, Haseeb; Yildiz, Vedat; Ruz, Patrick; Wiczer, Tracy; Rogers, Kerry A.; Awan, Farrukh T.; Bhat, Seema; Guha, Avirup; Kittai, Adam S.; Simonetti, Orlando P.; Raman, Subha V.; Wallace, Grant; Sanchez, Reynaldo; Bonsu, Janice M.; Gambril, John; Haddad, Devin; Mann, James; Wei, Lai; Kola-Kehinde, Onaopepo; Byrd, John C.; Woyach, Jennifer A.; Addison, Daniel; Medicine, School of MedicineImportance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, setting, and participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main outcomes and measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.Item Chemokine-Based Therapeutics for the Treatment of Inflammatory and Fibrotic Convergent Pathways in COVID-19(Springer Nature, 2021) Julian, Dana R.; Kazakoff, Megan A.; Patel, Akhil; Jaynes, Jesse; Willis, Monte S.; Yates, Cecelia C.; Medicine, School of MedicineCoronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 betacoronavirus and has taken over 761,426 American lives as of the date of publication and will likely result in long-term, if not permanent, tissue damage for countless patients. COVID-19 presents with diverse and multisystemic pathologic processes, including a hyperinflammatory response, acute respiratory distress syndrome (ARDS), vascular injury, microangiopathy, tissue fibrosis, angiogenesis, and widespread thrombosis across multiple organs, including the lungs, heart, kidney, liver, and brain. C-X-C chemokines contribute to these pathologies by attracting inflammatory mediators, the disruption of endothelial cell integrity and function, and the initiation and propagation of the cytokine storm. Among these, CXCL10 is recognized as a critical contributor to the hyperinflammatory state and poor prognosis in COVID-19. CXCL10 is also known to regulate growth factor-induced fibrosis, and recent evidence suggests the CXCL10-CXCR3 signaling system may be vital in targeting convergent proinflammatory and pro-fibrotic pathways. This review will explore the mechanistic role of CXCL10 and related chemokines in fibrotic complications associated with COVID-19 and the potential of CXCL10-targeted therapeutics for early intervention and long-term treatment of COVID-19-induced fibrosis.Item Complement System in Lung Disease(American Thoracic Society, 2014-10) Pandya, Pankita H.; Wilkes, David S.; Department of Microbiology & Immunology, IU School of MedicineIn addition to its established contribution to innate immunity, recent studies have suggested novel roles for the complement system in the development of various lung diseases. Several studies have demonstrated that complement may serve as a key link between innate and adaptive immunity in a variety of pulmonary conditions. However, the specific contributions of complement to lung diseases based on innate and adaptive immunity are just beginning to emerge. Elucidating the role of complement-mediated immune regulation in these diseases will help to identify new targets for therapeutic interventions.Item Comprehensive cardiac magnetic resonance T1, T2, and extracellular volume mapping to define Duchenne cardiomyopathy(Elsevier, 2023-07-31) Sunthankar, Sudeep D.; George‑Durrett, Kristen; Crum, Kimberly; Slaughter, James C.; Kasten, Jennifer; Raucci, Frank J., Jr.; Markham, Larry W.; Soslow, Jonathan H.; Pediatrics, School of MedicineBackground: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Cardiac magnetic resonance (CMR) parametric mapping sequences offer insights into disease pathophysiology. We propose a novel approach by leveraging T2 mapping in conjunction with T1 and extracellular volume (ECV) mapping to perform a virtual myocardial biopsy. While previous work has attempted to describe myocardial changes in DMD, our inclusion of T2 mapping enables comprehensive categorization of myocardial tissue characteristics of fibrosis, edema, and fat to better understand the pathological composition of the myocardium with disease progression. Methods: DMD patients (n = 49; median: 12 years-old) underwent CMR, including T1, T2, and ECV. Categories were defined as normal, isolated high T1 (normal ECV, high T1, normal T2), fibrosis (high ECV, normal or high T1, normal T2), edema (normal or high ECV, normal or high T1, high T2), fat (normal ECV, low T1, high T2) or fibrofatty (high ECV, low T1, high T2). Results: Median left ventricular ejection fraction (LVEF) was 59% with 27% having LVEF < 55%. Those with normal LVEF and no late gadolinium enhancement (37%) were younger in age (10.5 ± 2.6 vs. 15.0 ± 4.3 years-old, p < 0.001). Native T1 was elevated in at least one slice in 82% of patients. Those with high T2 at any slice (27%) were older (p = 0.005) and had lower LVEF (p = 0.005) compared with subjects with normal T2 (73%). The most common myocardial characterization was fibrosis (43%) followed by isolated high T1 (24%). Of the 13 with high T2, ten were categorized as edema, two as fibrofatty, and one as fat. Conclusion: CMR parametric mapping sequences offer insights into Duchenne cardiomyopathy pathophysiology, which should drive development of therapeutic interventions aimed at these targets. Myocardial fibrosis is common in DMD. Patients with elevated T2 were older and had lower LVEF. Though fat infiltration was present, the majority of subjects with elevated T2 met criteria for myocardial edema.