scholarly journals Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice

2020 ◽  
Vol 295 (36) ◽  
pp. 12605-12617
Author(s):  
Mathias Hohl ◽  
Manuel Mayr ◽  
Lisa Lang ◽  
Alexander G. Nickel ◽  
Javier Barallobre-Barreiro ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Marker Genes ◽  
Type Iii Collagen ◽  
Type I ◽  
Ecm Remodeling ◽  
Myocyte Hypertrophy

In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. In vitro, both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD–mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 μmol/mg tissue/min; CatA-TG, 8.62 μmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 μm; CatA-TG, 21.9 μm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 μl; CatA-TG, 61.9 μl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.

scholarly journals Effects of paeonol on proliferation and collagen synthesis of rat cardiac fibroblasts induced by aldosterone

2021 ◽  
Vol 16 (2) ◽  
pp. 42-48
Author(s):  
Qian Xu ◽  
Li Na Wang ◽  
Jing Yi Zhao ◽  
Yan Hong Xiao ◽  
Chao Du
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Neonatal Rat ◽  
Type Iii Collagen ◽  
Type I ◽  
Rt Pcr ◽  
Tgf Β1

The aim of this study was to explore the possible molecular mechanisms of paeonol in preventing ventricular remodeling. The cell viability of neonatal rat cardiac fibroblasts was detected by the method of MTT. RT-PCR and Western blot were used to measure the expression of TGF-β1, type I collagen and type III collagen. After treating the cardiac fibroblasts with paeonol, the cell viability decreased (p<0.01), and the expression of TGF-β1, type I collagen and types III collagen was significantly reduced (p<0.01). Thus, paeonol can inhibit the proliferation of fibroblast cells induced by aldosterone. The molecular mechanism is related to the down-regulation of TGF-β1 and type I and III collagen gene expression.

Adenylyl cyclase activity and function are decreased in rat cardiac fibroblasts after myocardial infarction

2007 ◽  
Vol 293 (5) ◽  
pp. H3216-H3220 ◽  
Author(s):  
James S. Swaney ◽  
Hemal H. Patel ◽  
Utako Yokoyama ◽  
N. Chin Lai ◽  
Matthew Spellman ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Adenylyl Cyclase ◽  
Collagen Synthesis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Collagen Production ◽  
And Function ◽  
Expression And Activity

Myocardial infarction (MI) results in left ventricular remodeling (e.g., ventricular hypertrophy, dilatation, and fibrosis). Fibrosis contributes to increased myocardial stiffening, impaired ventricular filling and function, and reduced cardiac output. Adenylyl cyclase (AC) expression and activity are reduced in animal models of heart failure. Stimulation of AC can inhibit extracellular matrix production in isolated cardiac fibroblasts; however, a role for reduced AC expression and activity in fibrosis associated with cardiac remodeling after chronic MI has never been determined. We tested the hypothesis that AC expression and activity are reduced in cardiac fibroblasts after chronic (18 wk) MI. Rats underwent coronary artery ligation or sham surgery (control), and echocardiography was used to assess left ventricular remodeling 1, 3, 5, 7, 10, 12, and 18 wk after surgery. Cardiac fibroblasts were isolated from the noninfarcted myocardium and compared for differences in AC activity and collagen synthesis. End-diastolic dimension was increased [control: 0.76 ± 0.02 cm and MI: 1.0 ± 0.02 cm (means ± SE), P < 0.001] and fractional shortening was decreased (control: 44 ± 2% and MI: 17 ± 2%, P < 0.001) in MI compared with control rats. Basal and forskolin-stimulated cAMP production were decreased by 90% and 93%, respectively, and AC5/6 expression was decreased 39% in fibroblasts isolated from MI rats compared with sham controls. Serum-stimulated collagen production was increased twofold and forskolin-mediated inhibition of collagen synthesis was reduced in fibroblasts from MI rats compared with controls. Our data demonstrate that AC expression and activity are reduced and collagen production is increased in cardiac fibroblasts of rats after MI.

scholarly journals 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

2014 ◽  
Vol 307 (5) ◽  
pp. H752-H761 ◽  
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.

Effect of angiotensin type I–receptor blockade on left ventricular remodeling in pressure overload hypertrophy

2001 ◽  
Vol 7 (4) ◽  
pp. 342-347 ◽  
Author(s):  
Songsak Kiatchoosakun ◽  
Earl Lawrence ◽  
Shigekazu Nakada ◽  
Joseph Restivo ◽  
Richard A. Walsh ◽  
...  
Keyword(s):  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Type I ◽  
Receptor Blockade ◽  
Angiotensin Type

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

2010 ◽  
Vol 298 (5) ◽  
pp. H1415-H1425 ◽  
Author(s):  
Sih Min Tan ◽  
Yuan Zhang ◽  
Kim A. Connelly ◽  
Richard E. Gilbert ◽  
Darren J. Kelly
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Artery Ligation ◽  
Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

Ventricular remodeling in a mouse model of myocardial infarction

1998 ◽  
Vol 274 (5) ◽  
pp. H1812-H1820 ◽  
Author(s):  
Richard D. Patten ◽  
Mark J. Aronovitz ◽  
Luz Deras-Mejia ◽  
Natesa G. Pandian ◽  
George G. Hanak ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Body Weight ◽  
Mouse Model ◽  
Sham Group ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Body Weight Ratio ◽  
Right Ventricular Mass

We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation ( n = 22) or a sham procedure ( n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure ( P < 0.05), higher LV end-diastolic pressure ( P < 0.05), and lower peak first derivative of LV pressure (dP/d t, P < 0.05) than the sham group. Mice with moderate (<40%, n = 11) and large (≥40%, n = 11) MIs displayed increased LV mass-to-body weight ratio ( P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio ( P < 0.01). LV volumes were increased in the moderate-MI group ( P= 0.059 vs. sham group) and to a much greater extent in the large-MI group ( P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter ( P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter ( P< 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening ( P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.

Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure

1998 ◽  
Vol 275 (1) ◽  
pp. H250-H258 ◽  
Author(s):  
Ping Yue ◽  
Barry M. Massie ◽  
Paul C. Simpson ◽  
Carlin S. Long
Keyword(s):  
Heart Failure ◽  
Growth Factors ◽  
Regulatory Role ◽  
Type Iii Collagen ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Altered Expression ◽  
Myocyte Hypertrophy ◽  
Tnf Α ◽  
Tgf Β1

Growing evidence suggests that cardiac nonmyocyte cells may play an important regulatory role in the response to myocardial overload and injury via altered expression of paracrine products, such as cytokines and growth factors, but information concerning the cell-specific changes in the expression of these substances in heart-failure models is limited. Therefore, cardiac nonmyocytes were isolated from rats 1 day and 1 and 6 wk after left coronary artery ligation with resulting hemodynamic evidence of heart failure and in sham-operated control animals. mRNAs for tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, transforming growth factors (TGF)-β1 and TGF-β3, and type I and type III collagen were measured by Northern analyses. The temporal and quantitative relationships between the expression of these cytokines and collagen and myocyte hypertrophy were determined. mRNA expression of IL-1β was increased by 1.3-fold at 1 day and 1 wk, and expression of TNF-α, IL-1β, IL-6, TGF-β1, and TGF-β3 were increased by 1.4- to 2.1-fold at the 1-wk time point before returning toward baseline at 6 wk. There were significant correlations between the expression of these cytokines and the expression of types I and III collagen, which also peaked at 1 wk. Myocyte hypertrophy was seen first at 6 wk. These observations are consistent with a hypothesis that nonmyocyte cells play a regulatory role in the extracellular matrix changes during postinfarction remodeling and highlight the importance of examining cell-specific changes in gene expression and elucidating the role of cell-to-cell interactions within the myocardium.

scholarly journals Progressive chronic heart failure slows the recovery of microvascular O2 pressures after contractions in the rat spinotrapezius muscle

2010 ◽  
Vol 299 (6) ◽  
pp. H1755-H1761 ◽  
Author(s):  
Steven W. Copp ◽  
Daniel M. Hirai ◽  
Leonardo F. Ferreira ◽  
David C. Poole ◽  
Timothy I. Musch
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Chronic Heart Failure ◽  
Diastolic Pressure ◽  
Fiber Type ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Type I ◽  
Body Weight Ratio

Chronic heart failure (CHF) induces muscle fiber-type specific alterations in skeletal muscle O2 delivery and utilization during metabolic transitions. As a result, the recovery of microvascular Po2 (PmvO2) is prolonged in slow-twitch skeletal muscle but not fast-twitch skeletal muscle in rats with CHF. We tested the hypothesis that CHF slows PmvO2 recovery in rat skeletal muscle of a mixed fiber-type analogous to human locomotory muscles and that the degree of slowing correlates with central indexes of heart failure. Healthy control [ n = 6, left ventricular end-diastolic pressure (LVEDP): 10 ± 1 mmHg], moderate CHF ( n = 6, LVEDP: 18 ± 2 mmHg), and severe CHF ( n = 4, LVEDP: 34 ± 2 mmHg) female Sprague-Dawley rats had their right spinotrapezius muscles (41% type I, 7% type IIa, and 52% type IIb and d/x) exposed, and PmvO2 was measured via phosphorescence quenching during 180 s of recovery from 180 s of electrically induced twitch contractions (1 Hz, 4–6 V). CHF progressively slowed the mean response time (MRT; the time to reach 63% of the overall dynamic response) of PmvO2 recovery (MRToff; control: 60.2 ± 6.9, moderate CHF: 72.8 ± 6.6, and severe CHF: 109.8 ± 6.6 s, P < 0.05 for all). MRToff correlated positively with central hemodynamic (LVEDP: r = 0.76, P < 0.01) and morphological (right ventricle-to-body weight ratio: r = 0.74, P < 0.01; and lung weight-to-body weight ratio: r = 0.79, P < 0.01) indexes of heart failure. The present investigation suggests that slowed PmvO2 kinetics during recovery in CHF constitutes a mechanistic link between impaired circulatory and metabolic recovery after contractions in CHF.

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