Abstract 415: Asporin Contributes to Reactive Interstitial Cardiac Fibrosis by Regulating Cardiac Fibroblast Activation

Cardiac fibrosis critically contributes to heart failure progression. Depending on the pathological insult, cardiac fibrosis either replaces necrotic cardiomyocytes or is reactive to cardiac fibroblast (CF) activation. The extracellular matrix (ECM) consists of various proteins and the role of fibrillar collagen has been well studied. However, the role of non-fibrillar ECM proteins in cardiac fibrosis is less clear. To explore the role of ECM in reactive cardiac fibrosis, we performed bioinformatic analysis on online available microarray GEO datasets from hearts of human hypertrophic cardiomyopathy patients and two mouse models of transverse aortic constriction and Angiotensin II (AngII) infusion. We found that 27 differentially expressed genes were common between the three datasets. Among these genes was the small leucine-rich proteoglycan Asporin (ASPN). ASPN was previously shown to be upregulated in the ECM of replacement fibrosis in porcine ischemia/reperfusion injury. However, not much is known about the role of ASPN in reactive interstitial fibrosis. We show that cardiac ASPN expression is enhanced in mice after short- and long-term AngII infusion compared to saline infusion. In resident CF isolated from adult mice, ASPN expression is upregulated by both AngII and TGF-β stimulation. Here, ASPN expression correlates with a gene signature of activated CFs including periostin ( postn ), α-smooth muscle actin ( acta2 ) and collagens I and III ( col1a1, col3a1 ), and with functional characteristics of activated CFs including proliferation, migration and collagen production. Modulating ASPN via siRNA in mouse resident CFs inhibits postn, acta2, col1a1 and col3a1 expression and total collagen production, indicating repressed CF activation upon ASPN knockdown. Taken together, ASPN may be an attractive novel target against reactive interstitial fibrosis.

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miR-21 in ischemia/reperfusion injury: a double-edged sword?

Physiological Genomics ◽

10.1152/physiolgenomics.00020.2014 ◽

2014 ◽

Vol 46 (21) ◽

pp. 789-797 ◽

Cited By ~ 56

Author(s):

Xialian Xu ◽

Alison J. Kriegel ◽

Xiaoyan Jiao ◽

Hong Liu ◽

Xiaowen Bai ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Hypoxia Inducible Factor ◽

Renal Interstitial Fibrosis ◽

Rna Molecules ◽

Programmed Cell Death 4 ◽

Proapoptotic Gene

MicroRNAs (miRNAs or miRs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the proapoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury; however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.

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Ischemia Reperfusion Injury Produces, and Ischemic Preconditioning Prevents, Rat Cardiac Fibroblast Differentiation: Role of KATP Channels

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd6020022 ◽

2019 ◽

Vol 6 (2) ◽

pp. 22 ◽

Cited By ~ 3

Author(s):

Kartika R. Pertiwi ◽

Rachael M. Hillman ◽

Coralie A. Scott ◽

Emily Lisa Chilton

Keyword(s):

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Cardiac Fibroblasts ◽

Ischemia Reperfusion ◽

Katp Channels ◽

Cardiac Fibroblast ◽

Time Control ◽

Paraffin Oil

Ischemic preconditioning (IPC) and activation of ATP-sensitive potassium channels (KATP) protect cardiac myocytes from ischemia reperfusion (IR) injury. We investigated the influence of IR injury, IPC and KATP in isolated rat cardiac fibroblasts. Hearts were removed under isoflurane anesthesia. IR was simulated in vitro by application and removal of paraffin oil over pelleted cells. Ischemia (30, 60 and 120 min) followed by 60 min reperfusion resulted in significant differentiation of fibroblasts into myofibroblasts in culture (mean % fibroblasts ± SEM in IR vs. time control: 12 ± 1% vs. 63 ± 2%, 30 min ischemia; 15 ± 3% vs. 71 ± 4%, 60 min ischemia; 8 ± 1% vs. 55 ± 2%, 120 min ischemia). IPC (15 min ischemia, 30 min reperfusion) significantly attenuated IR-induced fibroblast differentiation (52 ± 3%) compared to 60 min IR. IPC was mimicked by opening KATP with pinacidil (50 μM; 43 ± 6%) and by selectively opening mitochondrial KATP (mKATP) with diazoxide (100 μM; 53 ± 3%). Furthermore, IPC was attenuated by inhibiting KATP with glibenclamide (10 μM; 23 ± 5%) and by selectively blocking mKATP with 5-hydroxydecanoate (100 μM; 22 ± 9%). These results suggest that (a) IR injury evoked cardiac fibroblast to myofibroblast differentiation, (b) IPC attenuated IR-induced fibroblast differentiation, (c) KATP were involved in IPC and (d) this protection involved selective activation of mKATP.

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Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment

AJP Renal Physiology ◽

10.1152/ajprenal.00243.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. F658-F669 ◽

Cited By ~ 5

Author(s):

Heather M. Perry ◽

Nicole Görldt ◽

Sun-sang J. Sung ◽

Liping Huang ◽

Kinga P. Rudnicka ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Purinergic Signaling ◽

Smooth Muscle Actin ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Perivascular Cells ◽

Kidney Fibrosis ◽

Perivascular Cell ◽

Persistent Inflammation

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5′-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73−/− kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

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IGF-1 protects against angiotensin II-induced cardiac fibrosis by targeting αSMA

Cell Death and Disease ◽

10.1038/s41419-021-03965-5 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Sangmi Ock ◽

Woojin Ham ◽

Chae Won Kang ◽

Hyun Kang ◽

Wang Soo Lee ◽

...

Keyword(s):

Angiotensin Ii ◽

Molecular Mechanisms ◽

Low Dose ◽

Cardiac Fibrosis ◽

Interstitial Fibrosis ◽

Cardiac Fibroblasts ◽

Smooth Muscle Actin ◽

Coiled Coil ◽

Proliferation And Differentiation

AbstractThe insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.

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Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury

Biomedicines ◽

10.3390/biomedicines9030306 ◽

2021 ◽

Vol 9 (3) ◽

pp. 306

Author(s):

Maxime Rossi ◽

Kéziah Korpak ◽

Arnaud Doerfler ◽

Karim Zouaoui Boudjeltia

Keyword(s):

Reperfusion Injury ◽

Heme Oxygenase ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Macrophage Polarization ◽

Critical Role ◽

Kidney Injury ◽

Heme Oxygenase 1

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages.

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Peroxisome Proliferator-Activated Receptor-γIs Critical to Cardiac Fibrosis

PPAR Research ◽

10.1155/2016/2198645 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Huang-Jun Liu ◽

Hai-Han Liao ◽

Zheng Yang ◽

Qi-Zhu Tang

Keyword(s):

Immune Cells ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Receptor Superfamily ◽

Infarction Heart

Peroxisome proliferator-activated receptor-γ(PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγagonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγin various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγagonists for the clinical management of CVD.

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Role of Higenamine in Heart Diseases: A Mini-Review

Frontiers in Pharmacology ◽

10.3389/fphar.2021.798495 ◽

2022 ◽

Vol 12 ◽

Author(s):

Jianxia Wen ◽

Mingjie Li ◽

Wenwen Zhang ◽

Haoyu Wang ◽

Yan Bai ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Heart Disease ◽

Reperfusion Injury ◽

Cardiac Fibrosis ◽

Ischemia Reperfusion Injury ◽

Heart Diseases ◽

Ischemia Reperfusion ◽

Cardiac Ischemia

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

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Abstract 80: Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling following Ischemia/Reperfusion Injury

Circulation Research ◽

10.1161/res.115.suppl_1.80 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Meryl C Woodall ◽

Benjamin P Woodall ◽

Erhe Gao ◽

Xiying Shang ◽

Ancai Yuan ◽

...

Keyword(s):

Cardiac Function ◽

Knockout Mice ◽

Ischemia Reperfusion Injury ◽

Smooth Muscle Actin ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Cardiac Fibroblast

Decades of research have identified G Protein Coupled Receptor Kinase 2 (GRK2) as an important molecule that is upregulated in the cardiomyocyte after myocardial injury and during heart failure development. Research from our lab has convincingly demonstrated that myocyte-specific loss of GRK2 both before and after myocardial ischemic injury improves cardiac function and remodeling. Recent studies have reported that GRK2 is also upregulated in the cardiac fibroblast in the failing heart, suggesting a potential role for this molecule in the most abundant cell type in the heart. However, the in vivo implications of GRK2 expression in the fibroblast following cardiac stress remain a mystery. Tamoxifen inducible, fibroblast-specific GRK2 knockout mice (Col1α2CreER/GRK2flox) were treated with tamoxifen along with their control murine counterparts (GRK2flox alone) for 10 days to induce deletion of GRK2 in fibroblasts. Two weeks later mice were subjected to ischemia/reperfusion (I/R) injury via coronary artery occlusion for 30 minutes followed by periods of reperfusion. Fibroblast GRK2 knockout mice presented with preserved cardiac function 24 hours post-I/R compared to control mice as demonstrated by increased ejection fraction (58.1±1.8% vs. 48.7±1.2%, respectively, N=11-14, p=0.0005). GRK2 knockout mice also presented with decreased fibrosis in the infarcted area 72 hours following I/R injury as shown by Masson’s Trichrome staining. In line with decreased fibrosis, these mice also expressed decreased amounts of TGFβ1 and Collagen I. Additionally, α-smooth muscle actin expression is significantly diminished, indicating reduced fibroblast to myofibroblast transformation. These data suggest that GRK2 plays a key role up-stream in fibroblast activation and function in the ischemic heart and indicate that, like in the cardiomyocyte, inhibition of GRK2 in the cardiac fibroblast is a potential therapeutic target to limit cardiac dysfunction and remodeling after ischemic injury.

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