Fibrosis In Cardiovascular Diseases Research Articles

Targeting Myocardial Fibrosis-A Magic Pill in Cardiovascular Medicine?

Fibrosis, characterized by an excessive accumulation of extracellular matrix, has long been seen as an adaptive process that contributes to tissue healing and regeneration. More recently, however, cardiac fibrosis has been shown to be a central element in many cardiovascular diseases (CVDs), contributing to the alteration of cardiac electrical and mechanical functions in a wide range of clinical settings. This paper aims to provide a comprehensive review of cardiac fibrosis, with a focus on the main pathophysiological pathways involved in its onset and progression, its role in various cardiovascular conditions, and on the potential of currently available and emerging therapeutic strategies to counteract the development and/or progression of fibrosis in CVDs. We also emphasize a number of questions that remain to be answered, and we identify hotspots for future research.

The Latest Advances in Imaging Crosstalk Between the Immune System and Fibrosis in Cardiovascular Disease.

Inflammation and fibrosis are hallmarks of tissue repair processes and organ failure progression in cardiovascular diseases. Paradigm-shifting research on diverse immune cell populations within the cardiovascular system have enabled discovery of new biomarkers fostering development of diagnostic and therapeutic agents at the molecular level to better manage cardiovascular diseases. To date, a variety of molecular imaging agents have been developed to visualize the biomarkers expressed on immune cells and fibroblasts within their crosstalk network, which drives the pathogenesis of fibrosis triggered by both innate and adaptive immunity. Herein, key biomarkers upregulated in the immune-fibrosis axis are discussed. The promising molecular imaging agents to reveal this critical pathologic process are summarized.

Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.

Krüppel-like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)-induced adventitial pathologic changes. KLF15 expression was decreased in the vascular adventitia of Ang II-infused mice (1000 ng/kg/min, 14 d) and in adventitial fibroblasts (AFs) stimulated by Ang II (10-7 M). Adenovirus-mediated KLF15 overexpression normalized Ang II-induced vascular hypertrophy, increased collagen deposition, macrophage infiltration, and CCL2 and VCAM-1 expression. Interestingly, KLF15-ΔTAD (KLF15 with deletion of TAD at amino acids 132-152) overexpression showed no effect on the above pathologic changes. Similarly, perivascularly overexpression of KLF15 but not KLF15-ΔTAD in carotid arteries also attenuated Ang II-induced vascular inflammation and fibrosis. Furthermore, KLF15 overexpression after Ang II infusion rescued Ang II-induced vascular remodeling. CCL2 or VCAM-1-mediated monocyte and macrophage migration or adhesion to AFs in response to Ang II was negatively regulated by KLF15 through TAD. Ang II-enhanced Smad2/3 activation and adventitial migration, proliferation, and differentiation of AFs were suppressed by KLF15 but not KLF15-ΔTAD overexpression. Conversely, small interfering RNA knockdown of KLF15 aggravated Ang II-induced Smad2/3 activation and dysfunction of AFs. Luciferase, coimmunoprecipitation, and chromatin immunoprecipitation assay were used to demonstrate that interaction of KLF15 with Smad2/3 suppressed CCL2 expression through TAD. Mechanistically, activation of Ang II type 1 receptor/phospholipase Cγ 1/ERK1/2 signaling resulted in a decrease of KLF15 expression. In conclusion, these results demonstrate that KLF15 negatively regulates activation of AFs through TAD, which plays an important role in Ang II-induced adventitial inflammation and fibrosis.-Lu, Y.-Y., Li, X.-D., Zhou, H.-D., Shao, S., He, S., Hong, M.-N., Liu, J.-C., Xu, Y.-L., Wu, Y.-J., Zhu, D.-L., Wang, J.-G., Gao, P.-J. Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.

Colchicine, Inflammation and Fibrosis in Cardiovascular Disease: Merging Three Classical Tales

Colchicine, isolated from Colchicum autumnale, is a drug for acute gouty arthritis known from thousands of years whose use has survived to modernity. Over the past decades, the use for this very old drug extended beyond gout therapy. This was due to the advance in knowledge of (i) association of hyperuricemia and gout with cardiovascular disease, (ii) cytoskeletal microtubules (МТ), and (iii) anti-inflammatory and antifibrotic effects of colchicine, a classical MT-disassembling agent (antitubulin). Here, we present the Bulgarian contribution to colchicine potential in the therapy of cardiovascular disease that has emerged in the early 1970`s in the Laboratory of Electron Microscopy, Medical Institute, Varna, Bulgaria, studying the secretory (fibrogenic) function of vascular smooth muscle cells. From this time onward, low-dose colchicine (LoDoCo, 0.5 - 1.0 mg/daily) was increasingly administered orally for therapy of cardiovascular disease such as acute coronary syndromes, cardiac surgery postoperative atrial fibrillation, pericarditis, cardiac hypertrophy-associated heart failure, and systemic necrotizing vasculitis. Thus colchicine might be a new tool in the present therapeutic armamentarium for these diseases. It is simply an example of MT-disassembling drugs. Further studies will definitely be required before gaining real confidence in this kind of antitubulin therapy. This may lead to developing new and more specific antitubulins for therapy of cardiovascular disease. Biomed Rev 2017; 28: 105-110. Keywords: microtubules, tubulin, colchicine, antitubulins, cardiovascular diseases, inflammation, fibrosis

Differential proteomics reveals S100-A11 as a key factor in aldosterone-induced collagen expression in human cardiac fibroblasts

Aldosterone (Aldo) could induce cardiac fibrosis, a hallmark of heart disease. Aldo direct effects on collagen production in cardiac fibroblasts remain controversial. Our aim is to characterize changes in the proteome of adult human cardiac fibroblasts treated with Aldo to identify new proteins altered that might be new therapeutic targets in cardiovascular diseases. Aldo increased collagens expressions in human cardiac fibroblasts. Complementary, using a quantitative proteomic approach, 30 proteins were found differentially expressed between control and Aldo-treated cardiac fibroblasts. Among these proteins, 7 were up-regulated and 23 were down-regulated by Aldo. From the up-regulated proteins, collagen type I, collagen type III, collagen type VI and S100-A11 were verified by Western blot. Moreover, protein interaction networks revealed a functional link between a third of Aldo-modulated proteome and specific survival routes. S100-A11 was identified as a possible link between Aldo and collagen. Interestingly, CRISPR/Cas9-mediated knock-down of S100-A11 blocked Aldo-induced collagen production in human cardiac fibroblasts. In adult human cardiac fibroblasts treated with Aldo, proteomic analyses revealed an increase in collagen production. S100-A11 was identified as a new regulator of Aldo-induced collagen production in human cardiac fibroblasts. These data could identify new candidate proteins for the treatment of cardiac fibrosis in cardiovascular diseases. SignificanceS100-A11 is identified by a proteomic approach as a novel regulator of Aldosterone-induced collagen production in human cardiac fibroblasts. Our data could identify new candidate proteins of interest for the treatment of cardiac fibrosis in cardiovascular diseases.

Cardiac Fibrosis: The Fibroblast Awakens.

Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.

Matrix Metalloproteinase-9: Many Shades of Function in Cardiovascular Disease

Matrix metalloproteinase (MMP)-9, one of the most widely investigated MMPs, regulates pathological remodeling processes that involve inflammation and fibrosis in cardiovascular disease. MMP-9 directly degrades extracellular matrix (ECM) proteins and activates cytokines and chemokines to regulate tissue remodeling. MMP-9 deletion or inhibition has proven overall beneficial in multiple animal models of cardiovascular disease. As such, MMP-9 expression and activity is a common end point measured. MMP-9 cell-specific overexpression, however, has also proven beneficial and highlights the fact that little information is available on the underlying mechanisms of MMP-9 function. In this review, we summarize our current understanding of MMP-9 physiology, including structure, regulation, activation, and downstream effects of increased MMP-9. We discuss MMP-9 roles during inflammation and fibrosis in cardiovascular disease. By concentrating on the substrates of MMP-9 and their roles in cardiovascular disease, we explore the overall function and discuss future directions on the translational potential of MMP-9 based therapies.

30 GENERATION OF CLONED TRANSGENIC GOATS WITH CARDIAC SPECIFIC OVEREXPRESSION OF TRANSFORMING GROWTH FACTOR β1

Transforming growth factor β1 (TGF-β1) has a potent profibrotic function and is central to signaling cascades involved in interstitial fibrosis, which plays a critical role in the pathobiology of cardiomyopathy and contributes to diastolic and systolic dysfunction. In addition, fibrotic remodeling is responsible for generation of re-entry circuits that promote arrhythmias (Bujak and Frangogiannis 2007 Cardiovasc. Res. 74, 184–195). Due to the small size of the heart, functional electrophysiology of transgenic mice is problematic. Large transgenic animal models have the potential to offer insights into conduction heterogeneity associated with fibrosis and the role of fibrosis in cardiovascular diseases. The goal of this study was to generate transgenic goats overexpressing an active form of TGFβ-1 under control of the cardiac-specific α-myosin heavy chain promoter (α-MHC). A pcDNA3.1DV5-MHC-TGF-β1cys33ser vector was constructed by subcloning the MHC-TGF-β1 fragment from the plasmid pUC-BM20-MHC-TGF-β1 (Nakajima et al. 2000 Circ. Res. 86, 571–579) into the pcDNA3.1D V5 vector. The Neon transfection system was used to electroporate primary goat fetal fibroblasts. After G418 selection and PCR screening, transgenic cells were used for SCNT. Oocytes were collected by slicing ovaries from an abattoir and matured in vitro in an incubator with 5% CO2 in air. Cumulus cells were removed at 21 to 23 h post-maturation. Oocytes were enucleated by aspirating the first polar body and nearby cytoplasm by micromanipulation in Hepes-buffered SOF medium with 10 µg of cytochalasin B mL–1. Transgenic somatic cells were individually inserted into the perivitelline space and fused with enucleated oocytes using double electrical pulses of 1.8 kV cm–1 (40 µs each). Reconstructed embryos were activated by ionomycin (5 min) and DMAP and cycloheximide (CHX) treatments. Cloned embryos were cultured in G1 medium for 12 to 60 h in vitro and then transferred into synchronized recipient females. Pregnancy was examined by ultrasonography on day 30 post-transfer. A total of 246 cloned embryos were transferred into 14 recipients that resulted in production of 7 kids. The pregnancy rate was higher in the group cultured for 12 h compared with those cultured 36 to 60 h [44.4% (n = 9) v. 20% (n = 5)]. The kidding rates per embryo transferred of these 2 groups were 3.8% (n = 156) and 1.1% (n = 90), respectively. The PCR results confirmed that all the clones were transgenic. Phenotype characterization [e.g. gene expression, electrocardiogram (ECG), and magnetic resonance imaging (MRI)] is underway. We demonstrated successful production of transgenic goat via SCNT. To our knowledge, this is the first transgenic goat model produced for cardiovascular research. This work was supported by the Utah Science Technology and Research Initiative, Utah Multidisciplinary Arrhythmia Consortium.

50th anniversary of aldosterone.

This year marks the 50th anniversary of Simpson and Tait’s isolation of electrocortin (aldosterone) (Fig. 1). Five decades of research have yielded extensive insight into the biological actions mediated through this once elusive molecule, in particular, areas of sodium and potassium metabolism and the kidney. The history of discovery surrounding the mechanisms of regulation and action of aldosterone in the 1960s and 1970s provides a unique view of the birth of molecular biology and its consequent impact on the field of genomic research in the 1980s, 1990s, and the 21st century. Interestingly, recent areas of study have focused on the nongenomic effects of aldosterone and its involvement in inflammation and fibrosis in cardiovascular diseases. This has taken what might have at one time been considered a steroid hormone with a narrow pathological consequence into the realm of influencing widely prevalent diseases such as nephropathy, cardiomyopathy, and vasculopathy. Here, we provide a historic review of the discovery of aldosterone, emphasizing its widely expanding involvement in human disease. We begin describing the early years of aldosterone discovery including mention of its involvement in fibrosis by Selye. Next, we explore how molecular biology and genetics yield novel mechanisms of action and regulation. Finally, we revisit the area of nonclassical effects and the expanding involvement of aldosterone in common cardiovascular diseases.

Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis.

Remodeling of large and small arteries contributes to the development and complications of hypertension. The focus of this review is some of the mechanisms involved in the remodeling of small arteries in hypertension. In hypertension, changes in small artery structure are basically of 2 kinds: (1) inward eutrophic remodeling, in which outer and lumen diameters are decreased, media/lumen ratio is increased, and cross-sectional area of the media is unaltered; and (2) hypertrophic remodeling, in which the media thickens to encroach on the lumen, resulting in increased media cross-sectional area and media/lumen ratio. Growth, apoptosis, inflammation, and fibrosis contribute to vascular remodeling in hypertension. Apoptosis is gene-regulated cell death, with minimal membrane disruption and inflammation, that counters cell proliferation and fine-tunes developmental growth. Apoptosis has been reported in hypertension to be both increased and decreased in different tissues, including blood vessels. Inflammation, which may be low grade, probably plays an important role in triggering fibrosis in cardiovascular disease and hypertension. Vascular fibrosis entails accumulation of collagen, fibronectin, and other extracellular matrix components in the vessel wall and is an important aspect of extracellular matrix remodeling in hypertension. Associated with this, there may be increases in cell-matrix attachment sites (integrins) and changes in their topographical localization that may modulate arterial structure. Imbalance in matrix metalloproteinase/tissue inhibitors of metalloproteinases may contribute to alteration in collagen turnover and extracellular matrix remodeling. Chronic vasoconstriction may lead to embedding of the contracted vessel structure in a remodeled extracellular matrix, contributing to the inward remodeling of the blood vessel as smooth muscle cells are rearranged around a smaller lumen. The resulting remodeling of small arteries may initially be adaptive, but eventually it becomes maladaptive and compromises organ function, contributing to cardiovascular complications of hypertension.