Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy

2005 ◽  
Vol 83 (11) ◽  
pp. 999-1006 ◽  
Author(s):  
Mario Fritsch Neves ◽  
Farhad Amiri ◽  
Agostino Virdis ◽  
Quy N Diep ◽  
Ernesto L Schiffrin
Keyword(s):  
Inflammatory Markers ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Collagen Deposition ◽  
Ang Ii ◽  
Mobility Shift ◽  
Transcription Factor Activation ◽  
Mobility Shift Assay ◽  
Cell Adhesion Molecule 1

Activation of the renin–angiotensin–aldosterone system is associated with increased extracellular matrix and inflammatory markers in the cardiovascular system. We evaluated the effects of aldosterone antagonism on cardiovascular structure, collagen deposition, and expression of inflammatory markers in 2-week angiotensin (Ang) II-infused rats (120 ng·kg–1·min–1, s.c.) ± spironolactone or hydralazine (25 mg·kg–1·d–1). Aortic and cardiac collagen density was evaluated with Sirius red staining. NFκB and AP-1 were measured by a electrophoretic mobility shift assay, and ED-1 (macrophage marker) and vascular cell adhesion molecule-1 (VCAM-1) were measured by immunohistochemistry. Ang II increased blood pressure (176 ± 2 mmHg vs. 115 ± 1 mmHg in controls, p < 0.01), which was attenuated by spironolactone (147 ± 4 mmHg, p < 0.01) and prevented by hydralazine (124 ± 2 mmHg, p < 0.01). Ang II enhanced left ventricular interstitial collagen type I/III deposition (4.1% ± 0.1% vs. 3.1% ± 0.2%, p < 0.05), and this was attenuated by spironolactone but not hydralazine. Ang II-induced cardiac perivascular fibrosis was prevented by spironolactone and hydralazine. Ang II significantly increased cardiac AP-1 activity and ED-1 expression, which was prevented by spironolactone only. Ang II-enhanced NFκB activity, and VCAM-1 expression was reduced by spironolactone and hydralazine, whereas aortic hypertrophy was prevented by spironolactone and slightly reduced by hydralazine. In conclusion, blockade of mineralocorticoid receptors with spironolactone inhibited Ang II-induced aortic hypertrophy, cardiac transcription factor activation, upregulation of downstream inflammatory markers, and collagen deposition, thus preventing Ang II-induced cardiovascular damage.Key words: collagen, heart, aorta, spironolactone, inflammation.

scholarly journals Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis

2018 ◽  
Vol 315 (1) ◽  
pp. H92-H100 ◽  
Author(s):  
Lindsay T. McDonald ◽  
Michael R. Zile ◽  
Yuhua Zhang ◽  
An O. Van Laer ◽  
Catalin F. Baicu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Time Course ◽  
Pressure Overload ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Fibrillar Collagen ◽  
Collagen Deposition ◽  
Myocardial Stiffness ◽  
Insoluble Collagen

Myocardial fibrosis and the resultant increases in left ventricular stiffness represent pivotal consequences of chronic pressure overload (PO) that impact both functional capacity and the rates of morbid and mortal events. However, the time course and cellular mechanisms that underlie PO-induced fibrosis have not been completely defined. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that has been shown to be required for insoluble collagen deposition and increased myocardial stiffness in response to PO in mice. As macrophages are associated with increases in fibrillar collagen, the hypothesis that macrophages represent a source of increased SPARC production in the PO myocardium was tested. The time course of changes in the myocardial macrophage population was compared with changes in procollagen type I mRNA, production of SPARC, fibrillar collagen accumulation, and diastolic stiffness. In PO hearts, mRNA encoding collagen type I was increased at 3 days, whereas increases in levels of total collagen protein did not occur until 1 wk and were followed by increases in insoluble collagen at 2 wk. Increases in muscle stiffness were not detected before increases in insoluble collagen content (>1 wk). Significant increases in myocardial macrophages that coincided with increased SPARC were found but did not coincide with increases in mRNA encoding collagen type I. Furthermore, immunohistochemistry and flow cytometry identified macrophages as a cellular source of SPARC. We conclude that myocardial macrophages play an important role in the time-dependent increases in SPARC that enhance postsynthetic collagen processing, insoluble collagen content, and myocardial stiffness and contribute to the development of fibrosis. NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in left ventricular and myocardial stiffness represent pivotal consequences of chronic pressure overload. In this study a murine model of cardiac fibrosis induced by pressure overload was used to establish a time course of collagen expression, collagen deposition, and cardiac macrophage expansion.

Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats

2010 ◽  
Vol 298 (2) ◽  
pp. H608-H613 ◽  
Author(s):  
Lavinia Tran ◽  
Andrew R. Kompa ◽  
Will Kemp ◽  
Arintaya Phrommintikul ◽  
Bing H. Wang ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Intracellular Signaling ◽  
Cardiac Myocyte ◽  
Collagen Type I ◽  
Left Ventricular ◽  
High Dose ◽  
Type I ◽  
Urotensin Ii ◽  
Rock Inhibitor

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 ± 3.3 ms, U-II 118.0 ± 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 ± 0.19 ms, U-II 1.04 ± 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol·kg−1·h−1) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-α1(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10−7 to 10−5 M) elicited concentration-dependent inhibition of U-II (10−7 M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.

Abstract 48: Age-associated Imbalance of Vasorin/TGF-β1 Signaling in VSMC Facilitates Collagen Production

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mingyi Wang ◽  
Gianfranco Pintus ◽  
Roberta Giordo ◽  
Jing Zhang ◽  
Liqun Jiang ◽  
...  
Keyword(s):  
Arterial Wall ◽  
Collagen Type ◽  
Collagen Type I ◽  
In Vivo Studies ◽  
Physical Interaction ◽  
Type I ◽  
Ang Ii ◽  
Collagen Production ◽  
At1 Antagonist ◽  
Tgf Β1

Collagen deposition, a hallmark of arterial aging that resembles post-injury arterial restenosis, is perpetrated by angiotensin II (Ang II) signaling in arterial wall. Collagen aggregation at sites of arterial injury is regulated by the coordinated signaling of pro-fibrotic TGF-β1 and anti-fibrotic vasorin within VSMCs. The Ang II/TGF-β1/vasorin signaling relationship within VSMCs with aging, however, remains unknown. In vivo studies in old vs. young FXBN rats show that aortic transcription and translation of vasorin markedly decrease with aging. In vitro studies in VSMCs isolated from old vs. young aortae. Ang II-associated reduction of vasorin protein abundance in young VSMCs and age-associated changes in vasorin protein levels are reversed by the AT1 antagonist, Losartan (Los) (Figure). Dual immunolabeling and co-immunoprecipitation demonstrate that the co-incidence and physical interaction of vasorin and TGF-β1 within VSMCs are significantly decreased with aging. Importantly, exposure of young VSMCs to Ang II that increases p-SMAD2/3 and collagen type I production, mimicking old cells, and this effect is abolished or substantially mitigated by Los treatment, overexpression of ectopic vasorin, or exogenous recombinant human-vasorin protein. In contrast, exposure of old VSMCs to Los decreases p-SMAD2/3 and collagen type I production.Thus, an imbalance of the Ang II/TGF-β1/vasorin signaling cascade, a feature of the aged arterial wall, enhances the collagen production by VSMCs. Maintaining this signaling balance is a novel measure to retard adverse extracellular matrix remodeling, a determinant of arterial stiffening with aging. (MW and GP co-first authors)

P1626MicroRNA-21 deteriorates left ventricular reverse remodeling by promoting cardiac fibrosis in non-ischemic cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Watanabe ◽  
T Narumi ◽  
T Watanabe ◽  
T Aono ◽  
J Goto ◽  
...  
Keyword(s):  
Ischemic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Reverse Remodeling ◽  
Type I ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Left Ventricular Reverse Remodeling

Abstract Background Left ventricular reverse remodeling (LVRR) contributes to better outcomes in patients with non-ischemic cardiomyopathy (NICM). It is reported that LVRR is associated with progression of cardiac fibrosis. MicroRNAs (miRs) have emerged as powerful regulators of post-transcriptional gene expression. We focused on miR-21, which plays a key role in pathogenesis of fibrosis in multiple organs. The aim of this study was to clarify the effect of miR-21 on cardiac fibrosis and LVRR in patients with NICM. Methods We measured plasma miR-21 levels in 16 patients with NICM. LVRR was defined as increased LVEF by ≥10% and decreased LV end-diastolic diameter index by ≥10% from baseline data after optimal medication treatment at 1-year of follow-up. Further, we examined miR-21 expression and its potential role in cardiac fibrosis induced by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes (NRCMs). Results There were 12 patients without LVRR and 4 patients with LVRR. Plasma miR-21 levels were significantly higher in patients without LVRR compared with those with LVRR. In TAC mice heart, miR-21 levels were significantly increased and programmed cell death 4 (PDCD4), a main target of miR-21, was decreased. In vitro, miR-21 levels were significantly increased and its upstream transcriptional factor, activator protein 1 (AP-1), was activated by Ang II stimulation in NRCMs. After transfection of miR-21 specific inhibitor, PDCD4 levels were upregulated. Furthermore, AP-1 activity, expression of collagen type I, and α-smooth muscle actin levels were significantly decreased after miR-21 inhibition. Conclusions These findings suggested that miR-21/PDCD4/AP-1 feedback loop pathway was involved in LVRR in patients with NICM by promoting cardiac fibrosis. MiR-21 can be the therapeutic target in NICM.

Ectopic trypsin in the myocardium promotes dilated cardiomyopathy after influenza A virus infection

2014 ◽  
Vol 307 (6) ◽  
pp. H922-H932 ◽  
Author(s):  
Hai-Yan Pan ◽  
Hua-Mei Sun ◽  
Lu-Jing Xue ◽  
Min Pan ◽  
Yi-Ping Wang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Influenza A Virus ◽  
Trypsin Inhibitor ◽  
Influenza A ◽  
Collagen Type ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Ventricular Dilation

We have previously reported that ectopic trypsin in the myocardium triggers acute myocarditis after influenza A virus (IAV) infection. As myocarditis is a common precursor to dilated cardiomyopathy (DCM), the aim of the present study was to investigate the influence of trypsin on the progression of DCM after IAV infection. IAV-infected mice treated with saline or trypsin inhibitor were euthanized on days 0, 9, 20, 40 and 60 postinfection. Trypsin expression colocalized with myocardial inflammatory loci and IAV-induced myocarditis peaked on day 9 postinfection and alleviated by day 20 but persisted until day 60 postinfection, even though replication of IAV was not detected from day 20 postinfection. Similar time courses were observed for the activation of pro-matrix metalloproteinase (pro-MMP)-9 and expression of the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Degradation of collagen type I, proliferation of ventricular interstitial collagen, and expression of collagen type I and III mRNA increased significantly during acute and chronic phases; collagen type III mRNA increased more significantly than collagen type I mRNA. Cardiac function progressively deteriorated with progressive left ventricular dilation. The trypsin inhibitor aprotinin suppressed pro-MMP-9 activation and cytokine release, alleviated myocardial inflammation, and restored collagen metabolism during acute and chronic phases of myocarditis. This effectively prevented ventricular dilation and improved cardiac function. These results suggest that ectopic trypsin in the myocardium promoted DCM through chronic activation of pro-MMP-9, persistent induction of cytokines, and mediation of collagen remodeling. Pharmacological inhibition of trypsin activity might be a promising approach for the prevention of viral cardiomyopathy.

scholarly journals The Imbalance of MMP-2/TIMP-2 and MMP-9/TIMP-1 Contributes to Collagen Deposition Disorder in Diabetic Non-Injured Skin

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Zhou ◽  
Chao Yang ◽  
Shan Zhang ◽  
Zun-Xiang Ke ◽  
Dian-Xi Chen ◽  
...  
Keyword(s):  
High Glucose ◽  
Cell Types ◽  
Collagen Type I ◽  
Dermal Fibroblasts ◽  
Epidermal Keratinocytes ◽  
Type I ◽  
Collagen Deposition ◽  
Skin Cell ◽  
Treatment Of Diabetes ◽  
Injured Skin

The importance of the early diagnosis and treatment of diabetes and its cutaneous complications has become increasingly recognized. When diabetic non-injured skin was stained with Masson’s trichrome, its dermal collagen was found to be disordered, its density was variable, and it was dispersed or arranged in vague fascicles. The collagen type I sequencing results of RNA sequencing-based transcriptome analysis of three primary human skin cell types—dermal fibroblasts, dermal microvascular endothelial cells, and epidermal keratinocytes—under high glucose were analyzed. The results showed that both COL1A1 and COL1A2 mRNA expressions were reduced in human dermal fibroblasts (HDFs). The ratio of matrix metalloproteinase (MMP)-2/tissue inhibitors of metalloproteinase (TIMP)-2 and MMP-9/TIMP-1 in HDFs increased when treated with high glucose. By inhibiting MMP-2 and MMP-9 with SB-3CT, collagen deposition disorder of the skin in streptozotocin-induced diabetes mice was alleviated. The imbalance of MMP2/TIMP2 and MMP9/TIMP1 contributes to the non-injured skin disorder of collagen deposition in diabetes, suggesting a possibility for early treatment of diabetes skin complications.

scholarly journals Fibrosis biomarkers as a predictive tool for clinical outcome in PLNR14Del patients

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
SM Van Der Voorn ◽  
M Bourfiss ◽  
ASJM Te Riele ◽  
K Taha ◽  
MA Vos ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Data ◽  
Collagen Type ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Blood Collection ◽  
Type I ◽  
T Wave ◽  
Wave Inversion

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Netherlands Cardio Vascular Research Initiative (CVON): the Dutch heart foundation Background Mutations in phospholamban (PLN, most often PLNR14Del), a protein that regulates Ca2+ homeostasis in cardiomyocytes, are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN patients, which compromises cardiac contractility and predisposes to arrhythmogenicity. Collagen type I is the most abundant type of collagen in the heart (85%). During continuous collagen synthesis propeptides, like procollagen type I carboxy-terminal propeptide (PICP) and during collagen breakdown, C-terminal telopeptide collagen type I (ICTP), are released into the circulation. Clinically, detection of fibrosis occurs via echo or MRI, however difficulties arise when patchy fibrosis has to be detected. Purpose To investigate if PICP and ICTP levels in blood are useful predictive biomarkers for clinical outcome in PLN patients. Methods 78 serum and EDTA blood samples were collected on the same day from ACM diagnosed (n = 12), DCM diagnosed (n = 14) or non-classified (n = 52) PLN patients. PICP levels were measured with an ELISA assay and ICTP with a RIA. Clinical data were subtracted two years around blood collection from Redcap, a Dutch database with medical records from PLN patients. Data were not normally distributed, so Spearman’s correlation coefficient and Mann-Whitney test were used. Results Gender, age and PICP/ICTP ratios were similarly distributed between the subgroups. First, we checked if clinical data subtracted two years around blood collection provided reliable results regarding clinical outcome. Patients who underwent clinical testing  5.5 weeks around blood collection revealed that clinical data were in line with the best-fitted line of the linear regression and therefore provide reliable results. Next, the potential correlation of fibrosis biomarkers with electrical parameters was assessed. Increased PICP/ICTP ratios suggest a higher collagen deposition. Although there was no correlation with prolonged QRS duration (Rs 0.13, n = 62, ns), subgroup analysis showed a significant weak correlation for non-classified patients (Rs 0.32, n = 38, p = 0.05). No significant correlation was found for ACM or DCM patients; however, groups were rather small. PICP/ICTP ratio was significantly higher in patients with T wave inversion and premature ventricular contractions (PVCs) during an exercise tolerance test. A weak inverted correlation was found with left ventricular ejection fraction and PICP/ICTP (Rs -0.28, n = 23, ns), while moderate correlations between the ratio and end diastolic volume, and end systolic volume exist (both Rs 0.40, n = 23, p = 0.06). Conclusion High PICP/ICTP ratios correlate with clinical outcome in PLN patients, such as T wave inversion and PVCs. However, the size and heterogeneity of the patient group resulted in weak to moderate correlation coefficients and might therefore currently precludes to use PICP and ICTP levels as biomarker.

Epithelial-to-mesenchymal transition in fibrosis: Collagen type I expression is highly upregulated after EMT, but does not contribute to collagen deposition

2013 ◽  
Vol 319 (19) ◽  
pp. 3000-3009 ◽  
Author(s):  
Nynke A. Hosper ◽  
Paul P. van den Berg ◽  
Saskia de Rond ◽  
Eliane R. Popa ◽  
Martijn J. Wilmer ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Collagen Deposition ◽  
Mesenchymal Transition
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