Hypertension Fibrosis Research Articles

CTRP3 inhibits myocardial fibrosis through the P2X7R-NLRP3 inflammasome pathway in SHR rats.

Reducing hypertensive myocardial fibrosis is the fundamental approach to preventing hypertensive ventricular remodelling. C1q/TNF-related protein-3 (CTRP3) is closely associated with hypertension. However, the role and mechanism of CTRP3 in hypertensive myocardial fibrosis are unclear. In this study, we aimed to explore the effect of CTRP3 on hypertensive myocardial fibrosis and the potential mechanism. WKY and SHR rats were employed, blood pressure, body weight, heart weight, H/BW were measured, and fibrotic-related proteins, CTRP3 and Collagen I were tested in myocardium at 12 and 20 weeks by immunohistochemical staining and Western blotting, respectively. The results showed that compared with the WKY, SBP, DBP, mean arterial pressure and heart rate (HR) were all significantly increased in SHR at 12 and 20 weeks, while heart weight and H/BW were only increased at 20 weeks. Meanwhile, CTRP3 decreased, while Collagen I increased significantly in the SHR rat myocardium at 20 weeks, which compared to the WKY. Moreover, the expression of α-SMA increased from 12 weeks, Collagen I/III and MMP2/9 increased and TIMP-2 decreased until 20 weeks. In order to explore the function and mechanism of CTRP3 in hypertensive fibrosis, Angiotensin II (Ang II) was used to induce hypertension in primary neonatal rat cardiac fibroblasts in vitro . CTRP3 significantly inhibited the Ang II induced activation of fibrotic proteins, purinergic 2X7 receptor (P2X7R)-NLRP3 inflammasome pathway. The P2X7R agonist BzATP significantly exacerbated Ang II-induced NLRP3 inflammasome activation, which was decreased by the P2X7R antagonists A43079, CTRP3 and MCC950. CTRP3 expression was decreased in the myocardium of SHR rats, and exogenous CTRP3 inhibited Ang II-induced fibrosis in cardiac fibroblasts by regulating the P2X7R-NLRP3 inflammasome pathway, suggesting that CTRP3 is a potential drug for alleviating myocardial fibrosis in hypertensive conditions.

Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol.

Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD. Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan. REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Ang II (Angiotensin II)–Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury

Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II-induced fibrogenic responses in epithelial cells. Mechanistically, Ang II-activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.

Abstract P3127: Wnt1-inducible Signalling Pathway Protein 1 Contributes To Vascular Fibrosis By Promoting Fibroblasts Phenotypic Switch And Extracellular Matrix Deposition

Background: Vascular fibrosis is linked with many diseases, including hypertension. Upon pathophysiological stimulation, fibroblasts undergo phenotypic switch and increase extracellular matrix (ECM) synthesis and deposition. Wnt1-inducible signalling pathway protein 1 (WISP-1) is a growth factor implicated in fibrotic remodelling. We tested the hypothesis that WISP-1 induces cardiac fibroblast activation and increases ECM deposition, thereby contributing to vascular fibrosis in hypertension. Methods and Results: Primary human cardiac fibroblasts (HCFs) were treated with recombinant WISP-1. Western blotting analysis showed that WISP-1 treatment for 30 minutes activated Akt pathway (phospho-Akt:total-Akt, fold change: 1.33±0.14 vs. 1.00±0, n=9, P <0.05). WISP-1 induced Akt phosphorylation was inhibited by an integrin β1 blocking antibody (phospho-Akt:total-Akt, fold change, 0.52±0.12 vs. 1.00±0, n=5, P <0.05). WISP-1 treatment for 24 hours induced collagen 1 maturation in conditioned media and coincided with decreased meprin α metalloproteinase protein levels (fold change: 0.44±0.14 vs. 1.00±0, n=5, P <0.05). The collagen maturation was inhibited by a zinc-mediated proteinase inhibitor (GM6001) or an Akt inhibitor. Additionally, immunocytochemistry analysis illustrated that 24-hour WISP-1 treatment increased the percentage of α-smooth muscle actin-positive HCFs compared to the control (1.89±0.37 vs. 1.00±0, n=8, P <0.05). In vivo , WISP-1 knockout mice exhibited reduced collagen 1 content (0.39±0.09 vs. 1.19±0.25, n=5-7, P <0.05) and proteoglycan content (2.20±0.37 vs. 6.22±1.10, n=5-7, P <0.05,) in the perivascular area compared to their wild-type control after 28 days angiotensin II (1000ng/kg/min) infusion. Conclusions: WISP-1 activates cardiac fibroblasts via integrin β1-Akt pathway and meprin α metalloproteinase, thereby inducing fibroblast phenotypic switch and promoting collagen deposition. Deletion of WISP-1 alleviated hypertension induced vascular fibrosis in vivo . Modulation of WISP-1 levels may be beneficial for attenuating the effects of hypertension on vascular fibrosis, and could provide potential therapeutic targets in clinical treatment.

In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome.

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.

NOX5 EXPRESSION IN A VASCULAR SMOOTH MUSCLE CELL-SPECIFIC MANNER INDUCES FIBROBLAST PHENOTYPIC SWITCH AND PRO-FIBROTIC EFFECTS

Objective: Mice expressing human Nox5 (hNox5) in vascular smooth muscle cells (VSMC) exhibit redox-sensitive vascular dysfunction and cardio-renal fibrosis. Mechanisms underlying pro-fibrotic effects are unclear. Here we assessed whether hNox5 in VSMCs promotes fibroblast phenotypic changes leading to myofibroblast differentiation and pro-fibrotic/inflammatory responses. Design and method: Fibroblasts were cultured from wildtype (WT) and mice expressing hNOX5 in VSMC (Nox5+SM22+). Mice (20 weeks old) were infused with Ang II (600 ng/Kg/day) for 28 days and renal fibrosis/inflammation studied. Markers of myofibroblasts, pro-fibrotic and inflammatory phenotypes were assessed by qPCR and immunoblotting. Inflammatory infiltrate was assessed by FACS. Results: Fibroblasts isolated from Nox5+SM22+ mice exhibited increased mRNA expression of pro-fibrotic markers, such as Col1A1 (2-ddCt: 1.74 ± 0.16 vs. WT 0.67 ± 0.11), Col3A1 (2-ddCt: 1.74 ± 0.18 vs. WT 0.96 ± 0.24) and TIMP3 (2-ddCt: 2.65 ± 0.25 vs. WT 0.38 ± 0.07), p < 0.05. Myofibroblast phenotype (SMC) markers mRNA, aSMA (2-ddCt: 1.54 ± 0.05 vs. WT 0.78 ± 0.17) and Myocd (2-ddCt: 1.36 ± 0.17 vs. WT 0.39 ± 0.22) were also increased in fibroblasts from Nox5 mice, p < 0.05. In terms of inflammatory phenotype, we observed that mRNA expression of CD36 (2-ddCt: 1.37 ± 0.07 vs. WT 86 ± 0.24), TNFa (2-ddCt: 1.32 ± 0.2 vs. WT 0.71 ± 0.17) and TNFR1 (2-ddCt: 1.26 ± 0.04 vs. WT 1.02 ± 0.10) were increased, while CD68 expression was decreased (2-ddCt: 0.82 ± 0.11 vs. WT 1.36 ± 0.18) in fibroblasts from Nox5+SM22+ mice (p < 0.05). In Nox5 mice fibroblasts, key regulators of fibrosis such as ROS production and TGFb protein expression (AU: 1.8 ± 0.05 vs. WT 1.4 ± 0.06), as well as TGFbR2 gene expression (2-ddCt: 2.04 ± 0.17 vs. WT 0.57 ± 0.12), were increased (p < 0.05). Kidneys from Ang II-infused Nox5+SM22+ mice exhibited significant perivascular fibrosis and inflammatory cell infiltration compared to WT. Kidney expression of vimentin (AU: 1.01 ± 0.05 vs WT 0.85 ± 0.03) and aSMA (AU: 0.44 ± 0.03 vs WT 0.33 ± 0.01), markers of myofibroblast differentiation, were increased in Nox5 mice (p < 0.05). In kidneys from Nox5+SM22+ mice, increased frequencies of macrophage F4/80 + (%: 24 ± 2 vs WT 18 ± 1, p < 0.05). Conclusions: Our findings suggest that Nox5 in VSMCs influences fibroblast phenotypic switching to myofibroblasts that likely influences cardiovascular and renal fibrosis in hypertension.

DP1 (Prostaglandin D2 Receptor 1) Activation Protects Against Vascular Remodeling and Vascular Smooth Muscle Cell Transition to Myofibroblasts in Angiotensin II-Induced Hypertension in Mice.

Vascular smooth muscle cell (VSMC) phenotype transition plays an essential role in vascular remodeling. PGD2 (Prostaglandin D2) is involved in cardiovascular inflammation. In this study, we aimed to investigates the role of DP1 (PGD2 receptor 1) on VSMC phenotype transition in vascular remodeling after Ang II (angiotensin II) infusion in mice. VSMC-specific DP1 knockout mice and DP1flox/flox mice were infused with Ang II for 28 days and systolic blood pressure was measured by noninvasive tail-cuff system. The arterial samples were applied to an unbiased proteome analysis. DP1f/f Myh11 (myosin heavy chain 11) CREERT2 R26mTmG/+ mice were generated for VSMC lineage tracing. Multiple genetic and pharmacological approaches were used to investigate DP1-mediated signaling in phenotypic transition of VSMCs in response to Ang II administration. DP1 knockout promoted vascular media thickness and increased systolic blood pressure after Ang II infusion by impairing Epac (exchange protein directly activated by cAMP)-1-mediated Rap-1 (Ras-related protein 1) activation. The DP1 agonist facilitated the interaction of myocardin-related transcription factor A and G-actin, which subsequently inhibited the VSMC transition to myofibroblasts through the suppression of RhoA (Ras homolog family member A)/ROCK-1 (Rho associated coiled-coil containing protein kinase 1) activity. Moreover, Epac-1 overexpression by lentivirus blocked the progression of vascular fibrosis in DP1 deficient mice in response to Ang II infusion. Our finding revealed a protective role of DP1 in VSMC switch to myofibroblasts by impairing the phosphorylation of MRTF (myocardin-related transcription factor)-A by ROCK-1 through Epac-1/Rap-1/RhoA pathway and thus inhibited the expression of collagen I, fibronectin, ED-A (extra domain A) fibronectin, and vinculin. Thus, DP1 activation has therapeutic potential for vascular fibrosis in hypertension.

Exercise intervention prevents early aged hypertension-caused cardiac dysfunction through inhibition of cardiac fibrosis.

Background: An inappropriate accumulation of fibrillar collagen is a common pathologic feature of early aged hypertensive heart disease, but little information regarding the effects of exercise training on cardiac fibrosis in hypertension is available. The purpose of this study was to evaluate the effects of exercise training on cardiac fibrotic pathways in early aged hypertensive rats.Methods: Masson’s trichrome staining and Western blotting were performed on the excised left ventricle from twenty male spontaneously hypertensive rats at age of 48 weeks, which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on a treadmill running occurred 5 days/week for 60 min/day, for 12 weeks), and from age-matched male Wistar–Kyoto normotensive controls (WKY).Results: Interstitial fibrosis was reduced in the SHR-Ex group when compared with the SHR group. The fibrotic-related protein levels of AT1R, FGF23, LOX-2, TGF-β, CTGF, p-Smad 2/3, MMP-2/TIMP-2, MMP-9/TIMP-1, uPA and collagen I were decreased in the SHR-EX group, when compared with the SHR group.Conclusions: Exercise training suppresses early aged hypertensive heart-induced LOX-2/TGF-β-mediated fibrotic pathways associated with decreasing AT1R and FGF23, which might provide a new therapeutic effect for exercise training to prevent adverse cardiac fibrosis and myocardial abnormalities in early aged hypertension.

Assessment of Left Ventricle Myocardial Function in Hypertensive Patients Using Three-Dimensional Speckle-Tracking Echocardiography (3D-STE)

Background: Increased myocardial fibrosis in hypertension leads to abnormalities in left ventricular diastolic function. 3D-speckle-tracking imaging (3D-STI) is a primary imaging modality used to detect early changes in the left ventricle (LV). The aim of this study was to assess the left ventricular myocardial function in hypertensive patients using 3D-speckle tracking imaging (3D-STI). Methods and Results: A case control, nonintervention, descriptive study was conducted in the Department of Ultrasound Diagnosis of Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (Wuhan, Hubei, China). The study subjects included 64 patients with hypertension (HT) and, as control group, 44 normotensives. HT patients were divided into HT-I group (SBP of 130-139 mmHg or DBP of 80-89 mmHg, and HT-II group (SBP >140 mmHg or DBP >90 mmHg). In this study, LV geometry and function were assessed using conventional 2D- and 3D-echocardiography in a total of 108 consecutive subjects. LV volumes, global and regional strains were measured using 3D-STI. LV ejection fraction (LVEF) was in normal range in three groups, but in general, it slightly decreased in HT-II patients, compared with control and HT-I groups (62.5±2.1%, 68.0±2.2%, and 67.5±1.3%, respectively, P=0.00). Global systolic strain demonstrated a significant decrease in GLS, GCS, and GRS in the HT-II group, compared with control and HT-I groups. All regional strain parameters (longitudinal, circumferential, and radial) significantly decreased in HT-II patients, compared with control and HT-I groups. Conclusion: A significant deterioration of global LV systolic functions is found in hypertensive patients with well-preserved LVEF, especially in patients with hypertension stage II.

Abstract P252: Smooth Muscle At1a Receptor Mediates Perivascular Fibrosis In Angiotensin Ii-infused Mice

Angiotensin II (Ang II) signaling via AT1 receptor has been shown to play a critical role in the pathogenesis of hypertension, cardiovascular hypertrophy and fibrosis. We have demonstrated that ADAM17 expressed in vascular smooth muscle cells (VSMC) mediates EGF receptor activation and promotes cardiac hypertrophy and perivascular fibrosis induced by Ang II. It is conceivable that Ang II signaling in VSMCs specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. In a recent study, deficiency of smooth muscle AT1a receptors results in diminished hypertension and protection from cardiac hypertrophy induced by Ang II. However, we have limited understanding whether smooth muscle AT1a receptors affects hypertensive fibrosis in vasculature. Thus, this study was designed to elucidate the roles of the AT1a receptor in VSMCs in cardiovascular remodeling including fibrosis during Ang II stimulation using VSMC AT1a receptor deficient mice. To delete the AT1a receptor from VSMCs, we crossed C57BL/6 transgenic mouse lines expressing Cre recombinase under the control of the sm22α promoter (KIsm22α-Cre). Male AT1a flox/flox KIsm22α-Cre+/- (SMKO) and Controls (AT1a flox/flox KIsm22α-Cre-/-) mice were infused with Ang II (1 μg/kg/min) for 2 weeks via osmotic mini-pump. In Control mice, Ang II infusion for 2 weeks induced cardiac hypertrophy indicated by heart-to-body weight ratio and echocardiogram. After 2 weeks of Ang II infusion, heart-to-body weight ratios were significantly increased in Control mice compared with AT1a SMKO mice (6.04 versus 4.89, respectively, p=0.032). Cardiac wall hypertrophy was seen in Controls after 2 weeks of Ang II infusion, which was attenuated in AT1a SMKOs. Control mice (n=5) showed vascular medial hypertrophy and perivascular fibrosis, whereas these phenotypic changes were attenuated in SMKO mice (n=4). In conclusion, AT1a receptors from VSMC could mediate Ang II-induced cardiovascular hypertrophy and perivascular fibrosis. Whether the data can be fully explained by the prevention of hypertension remains to be determined, the data contrast to the past manuscript showing a protective effect in AT1a flox/flox S100A4-Cre+/- mice (fibroblast silencing) with Ang II infusion.

Tenascin-C in Heart Diseases-The Role of Inflammation.

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.

36. ASSOCIATION OF ELECTROCARDIOGRAM PARAMETERS OF ATRIAL AND VENTRICULAR REMODELING WITH INTERSTITIAL FIBROSIS IN HYPERTENSIVE PATIENTS

Background: Cardiac remodeling is frequently seen in hypertensive patients and one of the causes of its process is interstitial fibrosis. Electrocardiogram (ECG) is a practical tool to detect impulse heterogeneity, reflecting fibrosis. Objective: To prove association of ECG parameters with interstitial fibrosis in hypertension which might be used to monitor effectiveness of therapies and prognosis. Methods: This is a cross-sectional study whose subjects were diagnosed with hypertension recruited from public healthcare from December 2018 until January 2019. Exclusion criteria were elderly (>65 years old), known coronary artery disease, heart failure, and valvular heart diseases. Association between ECG parameters which reflects atrial remodeling, represented by P-wave Dispersion (PWD), and ventricular remodeling, represented by QT dispersion (QTd), with degree of interstitial fibrosis, represented by soluble ST2 (SST2) from blood serum, which has been proven for detecting myocardial fibrosis, were analyzed using Spearman's correlation. Multivariate analysis was performed to adjust the outcome with age and sex. Results: From 36 subjects recruited, 24 (66.7%) subjects were female. The median age was 57 (45-65) years old. There were significant moderate correlations between SST2 with PWD (p 0.001; r 0.498), and QTd (p 0.002; r 0.462). After multivariate analysis, the correlation remains significant for PWD (p 0.001) and QTd (p 0.018). The moderate correlation between ECG parameters and SST2 maybe due to the fibrosis caused by myocardial damage in hypertension is subtler than heart failure. Conclusion: There are moderate correlations between ECG parameters of atrial and ventricular remodeling with interstitial fibrosis in hypertensive patients.

T-Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension.

Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.

Fragmented QRS as a Marker of Myocardial Fibrosis in Hypertension: a Systematic Review.

Hypertension cause damage in cardiac structure and induce pathological myocardial fibrosis that leads to hypertensive cardiomyopathy. A narrow fragmented QRS complex (fQRS) is associated with myocardial fibrosis and scar tissue in various cardiovascular diseases. It is also associated with myocardial fibrosis in hypertensive patients even in the absence of any structural heart diseases. This article aimed to demonstrate importance and usefulness of fQRS in hypertensive patients. Current evidence suggest that the frequency of fQRS is significantly higher in hypertensive patients compared to normotensives. Also, fQRS seems to be a predictor of left ventricular hypertrophy, increased systolic blood pressure, non-dipping, deterioration of the left ventricular geometry, and worse systolic and diastolic functions in hypertensive patients. As a simple and easy detectable electrocardiographic finding, fQRS may indicate myocardial fibrosis, uncontrolled blood pressure, and deteriorated cardiac structure in hypertensive patients even in the absence of other structural heart diseases, and may also be useful to predict high-risk hypertensives.

Regulation of Cardiac Mast Cell Maturation and Function by the Neurokinin-1 Receptor in the Fibrotic Heart

Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.

Маркеры системного воспаления и фиброза при гипертонической болезни и фибрилляции предсердий в сочетании с коморбидной эстракардиальной патологией

Маркеры системного воспаления и фиброза при гипертонической болезни и фибрилляции предсердий в сочетании с коморбидной эстракардиальной патологией

Current Opinion for Hypertension in Renal Fibrosis.

Arterial hypertension remains to be a serious problem with considerable morbidity and mortality worldwide in the present age. Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, renal failure, and heart failure. Hypertensive nephropathy is the second leading cause of death in chronic kidney disease (CKD) around the world. Long-time hypertension loading results in renal interstitial fibrosis, which is associated with aberrant activation of renal fibroblasts and excessive generation of extracellular matrix (ECM) proteins. Increasing evidence supported that proteinuria, tubular hypertrophy, oxidative stress, activation of renin-aldosterone-angiotensin system (RAAS), collagen turnover, chronic inflammation, and vasoactive substances synergistically contributed to the pathogenesis of hypertensive renal fibrosis. However, the mechanisms involving the pathogenesis of hypertensive renal fibrosis are complex and not fully understood. Also, the effective clinical therapy to halt or even reverse renal fibrosis in hypertension is still limited. In this chapter, we aimed to provide an overview of the main pathophysiologic and mechanistic features of renal fibrosis under hypertensive state. The completion of the studies in these directions would improve our understanding of renal fibrosis in hypertension and also help us better screen treatment strategies for preventing renal destruction associated with hypertension.

Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-κB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-α is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-κB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-α-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IκB phosphorylation and NF-κB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-α. We found that TNF-α-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-α-induced NF-κB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IκB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-α-induced IKK phosphorylation and IKK-β expression. However, Ac-SDKP had no effect on TNF-α-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-α activation of canonical, i.e., IKK-β-dependent, NF-κB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-β.

Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension.

Various hypertensive stimuli lead to exuberant adventitial collagen deposition in large arteries, exacerbating blood pressure elevation and end-organ damage. Collagen production is generally attributed to resident fibroblasts; however, other cells, including resident and bone marrow-derived stem cell antigen positive (Sca-1(+)) cells and endothelial and vascular smooth muscle cells, can produce collagen and contribute to vascular stiffening. Using flow cytometry and immunofluorescence, we found that adventitial Sca-1(+) progenitor cells begin to produce collagen and acquire a fibroblast-like phenotype in hypertension. We also found that bone marrow-derived cells represent more than half of the matrix-producing cells in hypertension, and that one-third of these are Sca-1(+). Cell sorting and lineage-tracing studies showed that cells of endothelial origin contribute to no more than one fourth of adventitial collagen I(+) cells, whereas those of vascular smooth muscle lineage do not contribute. Our findings indicate that Sca-1(+) progenitor cells and bone marrow-derived infiltrating fibrocytes are major sources of arterial fibrosis in hypertension. Endothelial to mesenchymal transition likely also contributes, albeit to a lesser extent and pre-existing resident fibroblasts represent a minority of aortic collagen-producing cells in hypertension. This study shows that vascular stiffening represents a complex process involving recruitment and transformation of multiple cells types that ultimately elaborate adventitial extracellular matrix.

Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ)

BackgroundPrevious studies have shown that the activation of advanced glycation end products (AGEs) contributed to the cardiac fibrosis in diabetic patients. Although it had been reported that statins have beneficial effects on cardiac fibrosis in hypertension and myocardial ischemia models, their effects on AGEs models have not been studied. We aimed to investigate the effects of atorvastatin (Ator) on the AGEs-induced cardiac fibrosis both in vitro and vivo. MethodsMale Sprague-Dawley rats were randomly divided into four groups: Control, AGEs, Ator or AGEs+Ator. The cardiac function was evaluated with the echocardiography at the second and the third month. Fibrosis area, α-SMA and RAGE expression in cardiac tissue were measured. For in vitro study, rat cardiac fibroblasts were treated with PD98059 (ERK inhibitor), Ator or Ator+GW9662 (PPAR-γ antagonist), and then were stimulated with AGEs. Fibroblasts proliferation, ERK1/2, phosphorylated ERK1/2, α-SMA, and RAGE expression were studied. ResultsCompared with the control group, in vivo treatment with Ator significantly retarded the AGEs-induced diastolic function and attenuated cardiac fibrosis, α-SMA, and RAGE over expression induced by AGEs. Consistently, Ator prominently downregulated RAGE and α-SMA, while inhibited phosphorylation of ERK1/2 and fibroblast proliferation induced by AGEs in vitro. The GW9662 neutralized these effects of Ator on cardiac fibroblasts stimulated by AGEs. ConclusionIn this study, we demonstrated that AGEs-induced fibroblast proliferation and differentiation were dependent on AGEs-RAGE-ERK1/2 pathway and that atorvastatin could block this pathway via activating PPAR-γ.