Statins Attenuate Fibrotic Manifestations of Cardiac Tissue Damage

: Cardiac fibrosis is a maladaptive condition secondary to cardiomyopathy caused by a wide spectrum of stimuli includingmyocardial infarction (MI), pressure overload, hyperglycemia, aging, and other factors.Despite having been supposed to be a reparative mechanism, the development of cardiac fibrosis can result inundesirable outcomes likedisruption of excitation-contraction coupling and ventricular hypertrophy leading finallyto heart failure (HF).Statins are known as potent cardioprotective agents widely used to control dyslipidemia; these drugs have exhibited protective effects against manifestations of cardiac fibrosis and hypertrophy.Cumulative evidence have suggested that statins attenuate the severity of fibrotic and hypertrophic manifestations of cardiac damage by affecting a variety of mechanisms like differentiation of myofibroblasts and cross-talk between cells in cardiac tissue as well as altering the expression and function of different molecules involved in cardiac remodelingincluding inflammatory cytokines and signaling molecules.It seems that statins can inhibit cardiac fibrosis and hypertrophy not only through their ability to inhibit hydroxymethylglutaryl-CoA reductase, but also by their pleiotropic properties.This review aims to discuss the effects of statins on molecular pathways involved inthe inhibition of fibrotic and hypertrophic remodeling in the heart, therebypotentially helping to recover proper cardiac size, plasticity, and functioning.

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Abstract 15607: Right Atrial Reservoir Strain Predicts Survival in Patients With Cardiac Amyloidosis

Circulation ◽

10.1161/circ.142.suppl_3.15607 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Peter Huntjens ◽

Kathleen Zhang ◽

Yuko Soyama ◽

Maria Karmpalioti ◽

Daniel Lenihan ◽

...

Keyword(s):

Cardiac Amyloidosis ◽

Ventricular Hypertrophy ◽

Cardiac Tissue ◽

Fold Increase ◽

Left Ventricular ◽

Right Atrial ◽

Chamber View ◽

All Cause Mortality ◽

And Function

Introduction: Myofibril deposition in amyloidosis diffusely may affect cardiac structure and function. Right ventricular involvement has been associated with adverse clinical outcome. However, the utility of right atrial (RA) function assessment by echocardiographic strain imaging is unclear. Hypothesis: We hypothesize that right atrial stain has prognostic value in cardiac amyloidosis. Methods: We studied 121 consecutive patients with cardiac amyloidosis: 18% had transthyretin and 79% had light chain amyloidosis. Cardiac amyloidosis was either confirmed by endocardial biopsy (36%) or by a combination of non-cardiac tissue biopsy and proof of left ventricular hypertrophy (64%). Speckle tracking peak RA reservoir strain was assessed based on 6 segments from the apical 4-chamber view. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic peak longitudinal RA strain was feasible in 109 patients (90%). 60 CA patients died during follow-up period. Peak longitudinal RA strain was reduced in cardiac amyloidosis non-survivors (8.1%) in comparison to survivors (18.3%, p<0.01), showing RA involvement in cardiac amyloidosis. Peak RA strain was significantly associated with survival (using median 12.5%) (p<0.001). Low peak longitudinal RA strain was associated with a 3.3-fold increase in mortality risk (95% confidence interval: 1.83 - 5.96). Conclusions: Reduced peak longitudinal RA strain was significantly associated with survival in patients with cardiac amyloidosis. RA reservoir function assessed by strain appears to be useful as a new means to predict prognosis in cardiac amyloidosis patients and has promise for clinical application.

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Abstract 1582: Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on Pressure Overloaded-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_351 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Zhongbing Lu ◽

John Fassett ◽

Xin Xu ◽

Xinli Hu ◽

Guangshuo Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Heart Association ◽

Left Ventricular ◽

Neonatal Rat ◽

Protective Effects ◽

Rat Cardiomyocytes ◽

Extracellular Adenosine ◽

Myocardial Oxidative Stress

Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A 1 receptors (A 1 R) and A 3 receptors(A 3 R) is not known. To test the hypothesis A 1 R and A 3 R can protect the heart against systolic overload, we exposed A 3 R gene deficient (A 3 R KO) mice and A 1 R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A 3 R KO attenuated 5 weeks TAC-induced left ventricular (LV) hypertrophy (ratio of ventricular mass/body weight increased to 7.6 ±0.3 mg/g in wild type (Wt) mice as compared with 6.3±0.4 mg/g in KO), fibrosis and dysfunction (LV ejection fraction decreased to 43±2.5% and 55±4.2% in Wt and KO mice, respectively). A 3 R KO also attenuated the TAC-induced increases of myocardial ANP and the oxidative stress markers 3-nitrotyrosine(3-NT ) and 4-hydroxynonenal. In addition, A 3 R KO significantly attenuated TAC-induced activation of multiple MAP kinase pathways, and the activation of Akt-GSK signaling pathway. In contrast, A 1 R-KO increased TAC-induced mortality, but did not alter ventricular hypertrophy or dysfunction compared to Wt mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction, and increased myocardial 3-NT, indicates that extracellular adenosine protects heart against TAC-induced ventricular oxidative stress and hypertrophy. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine (CADO) reduced cell area, protein synthesis, ANP and 3-NT. Antagonism of A3R significantly potentiated the anti-hypertrophic effects of CADO. Our data demonstrated that extracellular adenosine exerts protective effects on the overloaded heart, but A 3 R act counter to the protective effect of adenosine. The data suggest that selective attenuation of A 3 R activity might be a novel approach to attenuate pressure overload-induced myocardial oxidative stress, LV hypertrophy and dysfunction. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

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Abstract P153: Role of Nonreceptor Tyrosine Kinases in Cardiac Fibrosis in a Mouse Model of Pressure Overload Hypertrophy

Circulation Research ◽

10.1161/res.109.suppl_1.ap153 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Sundaravadivel Balasubramanian ◽

Harinath Kasiganesan ◽

Lakeya Quinones ◽

Yuhua Zhang ◽

Amy Bradshaw ◽

...

Keyword(s):

Tyrosine Kinases ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Heart Diseases ◽

Pressure Overload ◽

In Vivo Studies ◽

Survival Pathways ◽

And Function ◽

Nonreceptor Tyrosine Kinases

During prolonged hypertrophic insult to the myocardium, while the function of cardiomyocytes needs to be protected, the hyperactivation of cardiac fibroblasts has to be curbed to prevent fibrosis. Previously, we showed that integrin-mediated non-receptor tyrosine kinase (NRTK) activation is required for normal functioning of both cardiac fibroblasts and cardiomyocytes. We hypothesized that inhibition of NRTKs in cardiac fibroblasts without affecting cardiomyocytes would be beneficial to the stressed myocardium. Our initial studies using kinase inactive forms of Src, Pyk2 and FAK expressed adenovirally in isolated primary cardiac fibroblasts showed that the pro-fibrotic signaling events as studied by fibronectin and collagen deposition are downregulated. Our in vivo studies in mouse transverse aortic constriction (TAC) model suggest that dasatinib, a multikinase NRTK inhibitor administration via a peritoneally implanted mini-osmotic pump is able to preserve ventricular geometry and function and reduce the accumulation of fibrotic extracellular matrix (ECM) proteins upon 4 wk pressure overload. Data obtained from cell culture experiments with kinase inactive NRTKs and dasatinib suggest that NRTK inhibition is able to reduce the proliferation, migration and mitogenic signaling in cardiac fibroblasts without affecting the cell survival pathways in cardiomyocytes. These data indicate that NRTKs play a significant pro-fibrotic role in cardiac fibroblasts and curbing the activity of NRTKs could be a potential therapeutic approach to treat fibrosis in hypertrophic heart diseases.

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KS370G, a synthetic caffeamide derivative, improves left ventricular hypertrophy and function in pressure-overload mice heart

European Journal of Pharmacology ◽

10.1016/j.ejphar.2012.03.029 ◽

2012 ◽

Vol 684 (1-3) ◽

pp. 108-115 ◽

Cited By ~ 7

Author(s):

Yi-Chun Weng ◽

Cheng-Fung Chuang ◽

Sung-Ting Chuang ◽

Hsi-Lin Chiu ◽

Yueh-Hsiung Kuo ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Left Ventricular ◽

And Function

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Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00063.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. H752-H761 ◽

Cited By ~ 7

Author(s):

William M. Yarbrough ◽

Catalin Baicu ◽

Rupak Mukherjee ◽

An Van Laer ◽

William T. Rivers ◽

...

Keyword(s):

Pressure Overload ◽

Left Ventricular ◽

Lv Function ◽

Type I ◽

Matrix Remodeling ◽

Protective Effects ◽

Ecm Remodeling ◽

Hypertrophic Response ◽

Lv Mass ◽

And Function

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

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Anti-Inflammatory and Antioxidative Effects of Sumatriptan Against Doxorubicin-Induced Cardiotoxicity in Rat

ACTA MEDICA IRANICA ◽

10.18502/acta.v59i7.7020 ◽

2021 ◽

Author(s):

Mohammad Sheibani ◽

Hedyeh Faghir-Ghanesefat ◽

Yaser Azizi ◽

Tahmineh Mokhtari ◽

Hasan Yousefi‐Manesh ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Mortality Rate ◽

Cardiac Tissue ◽

The Body ◽

Male Rats ◽

Protective Effects ◽

Cardiac Damage ◽

Necrosis Factor Alpha ◽

Antioxidative Effects

The clinical use of doxorubicin as a potent chemotherapeutic agent is limited due to its dose-dependent cardiotoxicity. Oxidative stress and inflammatory pathways have a pivotal role in doxorubicin-induced cardiotoxicity. Sumatriptan, a 5-hydroxytryptamine (5-HT)1B/1D agonist that is mainly used to relieve migraine pain, has suggested exerting protective effects in numerous pathological conditions through antiinflammatory properties. The aim of the present study was to investigate the effects of sumatriptan on doxorubicin-induced cardiotoxicity and the contribution of anti-inflammation and antioxidative responses. Cardiotoxicity was induced by the administration of doxorubicin three times a week (2.5 mg/kg i.p) for two consecutive weeks on male rats. The animals were divided into four groups, including Control, Sumatriptan (0.1 mg/kg) received group, doxorubicin received group, and Doxorubicin+Sumatriptan (0.1 mg/kg) received group. Sumatriptan was administered 30 min before every injection of doxorubicin. On the last day of the second week, the body weight, mortality rate, electrocardiogram (ECG) and histopathological changes, cardiac inotropic study, and biochemical factors were evaluated. The loss of body weight, mortality rate, ECG parameters, reduction of papillary muscle contractility force as well as histopathological scores following administration of doxorubicin indicated severe cardiac damage. However, treatment with sumatriptan inhibited the functional and structural impairment induced by doxorubicin. In addition, sumatriptan could significantly reduce cardiac tissue levels of malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α), which were increased in the doxorubicin-treated rats. This study illustrated the protective effects of sumatriptan on decreasing doxorubicin-induced cardiac toxicity and mortality rate in part through inhibition of inflammatory and oxidative stress pathways.

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Abstract 423: Kinase Independent Signaling of PI3Kγ Mediates Cardiac Fibrosis

Circulation Research ◽

10.1161/res.119.suppl_1.423 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Maradumane L Mohan ◽

Lisa M Grove ◽

Mitchell A Olman ◽

Sathyamangla V Naga Prasad

Keyword(s):

Cardiac Fibrosis ◽

Cardiac Tissue ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Stress Fibers ◽

Independent Function ◽

Specific Expression ◽

Myofibroblast Phenotype

Phosphoinositide 3 Kinase γ (PI3Kγ) belongs to a family of lipid kinases genetic deletion of which leads to pressure overload induced cardiac fibrosis in mice. However, the mechanism by which PI3Kγ mediates cardiac fibrosis is unknown. Cardiac fibrosis is a key underlying cause of fatal heart failure. A well-known fibrogenic mechanism is the generation of myofibroblasts, which are characterized by overexpression of smooth muscle α-actin (αSMA). Myofibroblast is a fibrosis-effector cell that produces pro-fibrotic cytokines and exuberant extracellular matrix that leads to cardiac fibrosis. To evaluate the role of PI3Kγ in fibrotic phenotype, cardiac tissue lysates from 3 months old WT and PI3Kγ null (PI3Kγ -/- ) mice were assessed for the expression of αSMA. Interestingly, there is significant up-regulation of αSMA in PI3Kγ -/- in comparison to littermate controls (WT) even at baseline suggesting that loss of PI3Kγ predisposes the hearts towards fibrosis. To directly confirm that PI3Kγ -/- cardiac fibroblasts (CF) exhibit a myofibroblast phenotype even at baseline, CF were isolated from hearts of WT and PI3Kγ -/- mice and assessed for myofibroblast phenotype by immunostaining for αSMA in stress fibers. Fluorescence microscopy on the CF from PI3Kγ -/- mice showed intense immunostaining for αSMA with greater number of cells exhibiting αSMA in stress fibers when compared to CF from WT mice. Consistently, immunoblotting showed significantly higher αSMA protein levels in PI3Kγ -/- CF compared to WT CF suggesting that PI3Kγ -/- fibroblasts are “primed” to undergo myofibroblast differentiation. To determine the role of kinase-independent function of PI3Kγ in vivo, we generated unique mice lines with cardiomyocyte-specific expression of either kinase-dead PI3Kγ (PI3Kγ inact ) or constitutively active PI3Kγ ( Myr PI3Kγ) in the global PI3Kγ -/- (PI3Kγ inact /PI3Kγ -/- or Myr PI3Kγ/PI3Kγ -/- ) and measured αSMA. Surprisingly, abundance of αSMA protein is significantly reduced in PI3Kγ inact /PI3Kγ -/- when compared to WT and PI3Kγ -/- mice. These data reveal that kinase-independent function of PI3Kγ is a key component in the myocyte-initiated pathway that ultimately drives CF to become myofibroblasts uncovering a novel mechanism of regulating pro-fibrotic signals.

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Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800996115 ◽

2018 ◽

Vol 115 (31) ◽

pp. E7428-E7437 ◽

Cited By ~ 14

Author(s):

Reshma S. Baliga ◽

Michael E. J. Preedy ◽

Matthew S. Dukinfield ◽

Sandy M. Chu ◽

Aisah A. Aubdool ◽

...

Keyword(s):

Heart Failure ◽

Guanylyl Cyclase ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Left Ventricular ◽

Treatment Modalities ◽

Pharmacodynamic Profile ◽

Cgmp Signaling ◽

Synthase Inhibitor ◽

And Function

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3′,5′-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α−/−) or natriuretic peptide-responsive GC-A (GC-A−/−), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A−/− mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.

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Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation

International Journal of Molecular Sciences ◽

10.3390/ijms222312695 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12695

Author(s):

Iris Rosa Betz ◽

Sarah Julia Qaiyumi ◽

Madeleine Goeritzer ◽

Arne Thiele ◽

Sarah Brix ◽

...

Keyword(s):

Mouse Model ◽

Palmitoleic Acid ◽

Target Genes ◽

Cardiac Fibrosis ◽

Pyruvate Dehydrogenase Kinase ◽

Protective Effects ◽

Cardiac Damage ◽

Illumina Hiseq ◽

Physiological Cardiac Hypertrophy

Palmitoleic acid (C16:1n7) has been identified as a regulator of physiological cardiac hypertrophy. In the present study, we aimed to investigate the molecular pathways involved in C16:1n7 responses in primary murine cardiomyocytes (PCM) and a mouse model of isoproterenol (ISO)-induced cardiac damage. PCMs were stimulated with C16:1n7 or a vehicle. Afterwards, RNA sequencing was performed using an Illumina HiSeq sequencer. Confirmatory analysis was performed in PCMs and HL-1 cardiomyocytes. For an in vivo study, 129 sv mice were orally treated with a vehicle or C16:1n7 for 22 days. After 5 days of pre-treatment, the mice were injected with ISO (25 mg/kg/d s. c.) for 4 consecutive days. Cardiac phenotyping was performed using echocardiography. In total, 129 genes were differentially expressed in PCMs stimulated with C16:1n7, including Angiopoietin-like factor 4 (Angptl4) and Pyruvate Dehydrogenase Kinase 4 (Pdk4). Both Angptl4 and Pdk4 are proxisome proliferator-activated receptor α/δ (PPARα/δ) target genes. Our in vivo results indicated cardioprotective and anti-fibrotic effects of C16:1n7 application in mice. This was associated with the C16:1n7-dependent regulation of the cardiac PPAR-specific signaling pathways. In conclusion, our experiments demonstrated that C16:1n7 might have protective effects on cardiac fibrosis and inflammation. Our study may help to develop future lipid-based therapies for catecholamine-induced cardiac damage.

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Abstract 1: Sprr2b Drives Proliferation of Cardiac Fibroblasts by Relieving p53-mediated Cell Cycle Inhibition

Circulation Research ◽

10.1161/res.121.suppl_1.1 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Ryan M Burke ◽

Janet K Lighthouse ◽

Pearl J Quijada ◽

Ronald Dirkx ◽

Michael A Trembley ◽

...

Keyword(s):

Cell Cycle ◽

Cardiac Remodeling ◽

Cell Cycle Progression ◽

Cardiac Fibrosis ◽

Cardiac Tissue ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Primary Source ◽

Cell Cycle Checkpoint ◽

Cycle Progression

Pathological cardiac remodeling is initially a compensatory attempt to increase cardiac output, but ultimately leads to the development of fibrosis, a form of scarring that contributes to heart failure (HF). In contrast, physiological cardiac remodeling in response to exercise is not associated with the development of fibrosis and typically remains compensatory. Understanding how cardiac fibroblasts (CF), the primary source of extracellular matrix in the heart, respond to pathological and physiological cues might lead to novel approaches to limit the maladaptive effects of pathological cardiac remodeling. We performed RNA sequencing to define genes that are differentially regulated in CF during physiological (swimming) or pathological (pressure overload) remodeling. This study revealed that cardiac expression of the s mall pr oline r ich 2b ( Sprr2b) gene is restricted to CFs and is significantly elevated in disease and lost in exercise. We demonstrate that SPRR2B drives CF proliferation, but not myofibroblast differentiation, in response to pathological cues. SPRR2B facilitates an interaction between MDM2 and USP7, a nuclear deubiquitinase that leads to proteasomal degradation of p53. SPRR2B-USP7-MDM2 complex formation and p53 degradation is at least partially dependent upon phosphorylation of SPRR2B by Src-family NRTKs. SPRR2B thus relieves p53-mediated constraints on cell cycle progression in response to Src-dependent signaling, leading to CF accumulation. Importantly, SPRR2B expression is elevated in cardiac tissue from human HF patients relative to individuals without heart disease and positively correlates with a proliferative, activated gene expression profile in HF patient CF. Treatment of human HF fibroblasts with IGF-1/H 2 O 2 to mimic physiological cues significantly abrogated SPRR2B expression and increased expression of p53-dependent cell cycle checkpoint genes, which correlated with a less activated phenotype. Taken together, this study defines a unique tissue-specific role of Sprr2b in driving pathological CF cell cycle progression that may underlie the development of cardiac fibrosis.

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