scholarly journals MicroRNA as a Therapeutic Target in Cardiac Remodeling

2017 ◽  
Vol 2017 ◽  
pp. 1-25 ◽  
Author(s):  
Chao Chen ◽  
Murugavel Ponnusamy ◽  
Cuiyun Liu ◽  
Jinning Gao ◽  
Kun Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Diseases ◽  
Myocardial Remodeling ◽  
Cardiac Tissues ◽  
Rna Molecules ◽  
Mirnas Expression ◽  
The Impact

MicroRNAs (miRNAs) are small RNA molecules that contain 18–25 nucleotides. The alterations in their expression level play crucial role in the development of many disorders including heart diseases. Myocardial remodeling is the final pathological consequence of a variety of myocardial diseases. miRNAs have central role in regulating pathogenesis of myocardial remodeling by modulating cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response through multiple mechanisms. The balancing and tight regulation of different miRNAs is a key to drive the cellular events towards functional recovery and any fall in this leads to detrimental effect on cardiac function following various insults. In this review, we discuss the impact of alterations of miRNAs expression on cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response. We have also described the targets (receptors, signaling molecules, transcription factors, etc.) of miRNAs on which they act to promote or attenuate cardiac remodeling processes in different type cells of cardiac tissues.

scholarly journals Cardiac Fibroblast-Specific Knockout of PGC-1α Accelerates AngII-Induced Cardiac Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Hong-jin Chen ◽  
Xiao-xi Pan ◽  
Li-li-qiang Ding ◽  
Cheng-chao Ruan ◽  
Ping-jin Gao
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Heart Diseases ◽  
Pathological Process ◽  
Peroxisome Proliferator ◽  
Pathological State ◽  
Ros Scavenging ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Cardiac remodeling consisted of ventricular hypertrophy and interstitial fibrosis is the pathological process of many heart diseases. Fibroblasts as one of the major cells in the myocardium regulate the balance of the generation and degeneration of collagen, and these cells transform toward myofibroblasts in pathological state, contributing to the remodeling of the heart. Peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1α (PGC-1α) is vital to the function of mitochondria, which contributes to the energy production and reactive oxidative species (ROS)-scavenging activity in the heart. In this study, we found that fibroblast-specific PGC-1α KO induced cardiac remodeling especially fibrosis, and Angiotensin II (AngII) aggravated cardiac fibrosis, accompanied with a high level of oxidative stress response and inflammation.

Abstract 61: Ablation of BK Ca Channels Results in Cardiac Hypertrophy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Harpreet Singh ◽  
Kajol Shah ◽  
Devsena Ponnalagu ◽  
Sanjay Chandrasekhar ◽  
Andrew R Kohut ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Interventricular Septum ◽  
Wild Type

Expression and activation of the large conductance calcium and voltage-gated potassium (BK Ca ) channels encoded by Kcnma1 gene is shown to be vital in cardioprotection from ischemia-reperfusion injury. BK Ca channels present in SA node cells regulate the heart rate, and in blood vessels play an active role in vascular relaxation. However, the role of BK Ca in regulation of structure and function of the heart is not fully-established. Using Kcnma1 -/- mice, we have observed structural changes in cardiomyocytes and compromised cardiac function as compared to wild type mice. Absence of BK Ca resulted in significant increase in size of adult cardiomyocytes (from 7.95 + 0.1 um 2 to 9.68 + 0.1 um 2 , p < 0.01, n=480 cells each) and also increased cardiac fibrosis. Further to determine underlying signaling mechanisms in cardiac hypertrophy, we performed microarray analysis of RNAs isolated from wild type and Kcnma1 -/- mice (n=3) hearts. We found up regulation of a class of cardiac hypertrophy markers (myosin variants) and changes in the expression of several mitochondrial genes (such as ND4) directly associated with heart diseases in Kcnma1 -/- mice. To evaluate the functional consequence of absence of BK Ca , we performed high-resolution echocardiography on wild type and Kcnma1 -/- mice. Under anesthesia (1.5% isoflurane), left ventricle of Kcnma1 -/- mice showed significant reduction (p < 0.05) in ejection fraction (56 + 2 %, n=7) as compared to wild type (74 + 3 %, n=6) as well as fractional shortening (23 + 3 %, n=7, and 39 + 3 %, n=6, respectively). Similarly, right ventricle had a lower ejection fraction (35.7 + 4% vs 56.9 + 5 %, n > 5) in Kcnma1 -/- as compared to wild type mice. In agreement with our histopathology and microarray data, Kcnma1 -/- mice showed increased posterior wall thickness (0.75 + 0.3 mm vs 0.62 + 0.1 mm) and interventricular septum thickness (0.83 + 0.4 mm, n=7 vs 0.68 + 0.3 mm, n=6) . Together, these data imply that BK Ca plays a direct role in cardiac hypertrophy and cardiac function.

Knockout of the Prostaglandin E2 Receptor Subtype 3 Promotes Eccentric Cardiac Hypertrophy and Fibrosis in Mice

2016 ◽  
Vol 22 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Shuang Liu ◽  
Yawei Ji ◽  
Jian Yao ◽  
Xiaodan Zhao ◽  
Hu Xu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Messenger Rna ◽  
Cardiac Fibrosis ◽  
Glycogen Synthase ◽  
Mrna Level ◽  
Matrix Metalloproteinase 2 ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
The Impact ◽  
Subtype 3

Background: Prostaglandin E2 receptor subtype 3 (EP3), a Gi protein-coupled receptor activated by prostaglandin E2, plays a particular role in cardioprotection. This study aimed to investigate the impact of EP3 deletion on cardiac remodeling and further elucidate the related involvement of possible signaling pathways. Methods and Results: The animals used were EP3 receptor knockout (EP3KO) mice and wild-type (WT) litter mate controls at 16-18 weeks old. The high-resolution echocardiography and weight index indicated that eccentric cardiac hypertrophy might occur in EP3KO mice, which were having worse cardiac function than WT litter mates. Isolated adult myocytes from EP3KO hearts showed spontaneous lengthening. Cardiac fibrosis was observed in EP3KO mice through Masson trichrome staining. The elevated messenger RNA (mRNA) level in matrix genes and the reduced mRNA, protein, and activity levels of matrix metalloproteinase 2 (MMP-2) indicated an increased synthesis and suppressed degradation of matrix collagen in EP3KO mice. The phosphorylation level of extracellular signal-regulated kinase (ERK) 1/2 protein was reduced in the cardiac tissue of EP3KO mice, accompanied by no significant change in the protein level of total ERK1/2, total p38, phospho-p38, glycogen synthase kinase-3β (GSK3β), phospho-GSK3β, and calcineurin (CaN) as well as CaN activity. Conclusion: EP3 knockout in cardiac tissues could induce eccentric cardiac hypertrophy and cardiac fibrosis at 16-18 weeks old. These effects of EP3 knockout might be regulated through inactivating MAPK/ERK pathway and affecting the MMP-2 expression. Overall, PGE2-EP3 is necessary to maintain the normal growth and development of the heart.

scholarly journals Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yi Wang ◽  
Zhiheng Guo ◽  
Yongmei Gao ◽  
Ping Liang ◽  
Yanhong Shan ◽  
...  
Keyword(s):  
Survival Rate ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Erk Signaling ◽  
Ang Ii ◽  
Total Survival

Abstract Pregnancy-associated cardiomyopathy (PAH) represents a pregnancy-associated myocardial disease that is characterized by the progression of heart failure due to marked left ventricular systolic dysfunction. Compelling evidence has highlighted the potential of angiotensin (Ang) receptor inhibitors as therapeutic targets in PAH treatment. The present study aims to elucidate the molecular mechanisms underlying Ang II receptor inhibitor LCZ696 treatment in PAH. Initially, a PAH mouse model was induced, followed by intraperitoneal injection of LCZ696. Subsequently, cardiomyocytes and fibroblasts were isolated, cultured, and treated with Ang II and LCZ696, followed by detection of the total survival rate, cardiac injury, cardiac fibrosis and apoptosis. Moreover, in order to quantify the cardiac hypertrophy and fibrosis degree of cardiac fibroblasts, the expression levels of markers of cardiac hypertrophy (ANP, βMHC and TIMP2) and markers of fibrosis (collagen I, collagen III and TGF-β) were evaluated. Furthermore, the potential effect of LCZ696 on the extracellular signal-regulated kinase (ERK) signaling pathway was examined. The acquired findings revealed that LCZ696 increased the total survival rate of PAH mice, but decreased cardiac injury, cardiac fibrosis, and apoptosis in vitro. LCZ696 attenuated cardiac injury induced by Ang II through the inhibition the expression of markers of cardiac hypertrophy, fibrosis and apoptosis by inhibiting ERK phosphorylation in vivo and in vitro. Altogether, LCZ676 could potentially alleviate cardiac remodeling in mice with PAH via blockade of the ERK signaling pathway activation. Our findings suggest that LCZ696 could be a potential target for PAH therapy.

scholarly journals CD47 Deficiency Attenuates Isoproterenol-Induced Cardiac Remodeling in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Zhi Zuo ◽  
Ming-Yue Ji ◽  
Kun Zhao ◽  
Zhong-Ping Su ◽  
Peng Li ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Control Group ◽  
Tunel Staining ◽  
Cardiac Tissues ◽  
Ampk Signaling ◽  
Creatine Kinase Mb ◽  
Sterile Normal Saline

In this study, we investigated whether CD47 deficiency attenuates isoproterenol- (ISO-) induced cardiac remodeling in mice. Cardiac remodeling was induced by intraperitoneal (i.p.) injection of ISO (60 mg·kg-1·d-1 in 100 μl of sterile normal saline) daily for 14 days and was confirmed by increased levels of lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB), increased heart weight to body weight (HW/BW) ratios, and visible cardiac fibrosis. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were found to be significantly higher in the ISO group than in the control group, while superoxide dismutase (SOD) levels were suppressed in the ISO group. However, CD47 knockout significantly limited ISO-induced increases in LDH, CK-MB, and HW/BW ratios, cardiac fibrosis, oxidative stress, and apoptosis in the heart. In addition, CD47 deficiency also increased p-AMPK and LAMP2 expression and decreased HDAC3, cleaved Caspase-3, cleaved Caspase-9, LC3II, and p62 expression in cardiac tissues. In conclusion, CD47 deficiency reduced i.p. ISO-induced cardiac remodeling probably by inhibiting the HDAC3 pathway, improving AMPK signaling and autophagy flux, and rescuing autophagic clearance.

The impact of epigenetics on cardiovascular disease

2020 ◽  
Vol 98 (1) ◽  
pp. 12-22 ◽  
Author(s):  
Dimple Prasher ◽  
Steven C. Greenway ◽  
Raja B. Singh
Keyword(s):  
Cardiac Fibrosis ◽  
Mortality And Morbidity ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Novel Biomarkers ◽  
External Risk ◽  
And Function ◽  
The Impact

Mortality and morbidity from cardiovascular diseases (CVDs) represents a huge burden to society. It is recognized that environmental factors and individual lifestyles play important roles in disease susceptibility, but the link between these external risk factors and our genetics has been unclear. However, the discovery of sequence-independent heritable DNA changes (epigenetics) have helped us to explain the link between genes and the environment. Multiple diverse epigenetic processes, including DNA methylation, histone modification, and the expression of non-coding RNA molecules affect the expression of genes that produce important changes in cellular differentiation and function, influencing the health and adaptability of the organism. CVDs such as congenital heart disease, cardiomyopathy, heart failure, cardiac fibrosis, hypertension, and atherosclerosis are now being viewed as much more complex and dynamic disorders. The role of epigenetics in these and other CVDs is currently under intense scrutiny, and we can expect important insights to emerge, including novel biomarkers and new approaches to enable precision medicine. This review summarizes the recent advances in our understanding of the role of epigenetics in CVD.

Abstract 19335: Rescue of Cardiac Function Lost Due to Congenital Defect in Proteasome Heterogeneity

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Felix Trogisch ◽  
Franziska Koser ◽  
Andreas Jungmann ◽  
Oliver Müller ◽  
Markus Hecker ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Ubiquitin Proteasome System ◽  
Wild Type ◽  
Gene Encoding ◽  
Proteasome Subunit ◽  
Adult Mice ◽  
Pre Treatment ◽  
The Impact

The ubiquitin-proteasome system is a major regulator of protein homeostasis in health and disease by targeted proteolysis. Recent findings show that the heterogeneity of proteasome complexes is dynamically altered via elevated incorporation of non-essential proteasome subunits in the pathogenesis of cardiac remodeling. However, the impact of this regulatory event on cardiac remodeling is not known. Therefore, aim of the study was to determine the influence of the non-essential proteasome subunit Lmp2 on cardiac remodeling induced by chronic catecholamine exposure. Wild-type mice subjected to 30mg/kg isoproterenol for 7 days developed cardiac hypertrophy with increased cardiac function (fractional shortening/FS: +18% vs. pre-treatment). In hearts of these mice, Lmp2 showed increased abundance and incorporation in proteasome complexes. Adult mice lacking Lmp2 congenitally seem phenotypically indistinguishable from wild-types, but developed exacerbated cardiac hypertrophy with decreased cardiac function (FS: -27% vs. wt) upon continuous isoproterenol stimulation. Myocardial transfer of the gene encoding Lmp2 via adeno-associated virus in adult mice resulted in the expression of its processed form comparable to wild-type levels with no obvious phenotypic effects under unstimulated conditions. Upon catecholamine challenge, increasing levels of processed Lmp2 were detected in hypertrophied hearts, suggesting induced functional incorporation in proteasome complexes similar to observations previously made in wild-type animals. Re-expression of Lmp2 reduced the extent of cardiac remodeling in mice congenitally lacking this subunit and rescued cardiac function at least in part (FS: +13% vs. treated virus control). In conclusion, the study demonstrates for the first time that induced expression of the non-essential proteasome subunit Lmp2 is a regulatory mechanism of targeted proteolysis, which mitigates cardiac remodeling and contributes to maintaining cardiac function.

Chronic angiotensin-(1–7) prevents cardiac fibrosis in DOCA-salt model of hypertension

2006 ◽  
Vol 290 (6) ◽  
pp. H2417-H2423 ◽  
Author(s):  
Justin L. Grobe ◽  
Adam P. Mecca ◽  
Haoyu Mao ◽  
Michael J. Katovich
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Cardiac Hypertrophy ◽  
Cross Sections ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Collagen Deposition ◽  
Sprague Dawley ◽  
Artery Cannulation ◽  
Blood Pressure Responses

Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1–7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery and were implanted with a deoxycorticosterone acetate (DOCA) pellet. DOCA animals had their drinking water replaced with 0.9% saline solution. A subgroup of DOCA-salt animals was implanted with osmotic minipumps, which delivered angiotensin-(1–7) chronically (100 ng·kg−1·min−1). Control animals underwent sham surgery and were maintained on normal drinking water. Blood pressure was measured weekly with the use of the tail-cuff method, and after 4 wk of treatment, blood pressure responses to graded doses of angiotensin II were determined by direct carotid artery cannulation. Ventricle size was measured, and cross sections of the heart ventricles were paraffin embedded and stained using Masson's Trichrome to measure interstitial and perivascular collagen deposition and myocyte diameter. DOCA-salt treatment caused significant increases in blood pressure, cardiac hypertrophy, and myocardial and perivascular fibrosis. Angiotensin-(1–7) infusion prevented the collagen deposition effects without any effect on blood pressure or cardiac hypertrophy. These results indicate that angiotensin-(1–7) selectively prevents cardiac fibrosis independent of blood pressure or cardiac hypertrophy in the DOCA-salt model of hypertension.

Abstract 17087: VNS Induced Early Suppression of the Excessive Inflammatory Response May Contribute to its Beneficial Effects on Chronic Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Akiko Nishizaki ◽  
Keita Saku ◽  
Takuya Kishi ◽  
Tomomi Ide ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Inflammatory Response ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Heart Weight ◽  
Lv Function ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Excessive Inflammatory Response

Background: The inflammatory response plays a pivotal role in the pathogenesis of chronic heart failure (CHF). Although vagal nerve stimulation (VNS) improves CHF, the central mechanism remains unclear. Since VNS exerts powerful anti-inflammatory effects, we investigated how VNS impacts on the inflammatory regulation and the development of CHF. Methods: In 8 weeks old Sprague-Dawley rats, we created large myocardial infarction (MI) and started VNS 2 weeks after MI. We adjusted the intensity of VNS below the threshold of bradycardia (20 Hz, 1.5±0.9 volts, 10 sec on, 50 sec off). In the first group (EARLY) (CHF: n=8, VNS: n=13), we continued VNS for 3 days and evaluated the early impact of VNS on inflammation on the 3rd day. In the second group (LATE) (CHF: n=13, VNS: n=13), we continued VNS for 4 weeks and evaluated cardiac remodeling and function on the last day. Results: In EARLY, hemodynamic parameters or plasma BNP as an index of CHF did not change significantly. In contrast, VNS halved the invasion of CD 68 positive cells in the left ventricle (LV) (CHF: 295.1±142.1, VNS: 110.7±59.6 counts/mm2, p<0.01), and markedly reduced interleukin-1β (IL-1β) not only in plasma (CHF: 75.7±27.6, VNS: 32.9±6.8 pg/mL, p<0.01) but also in the heart (CHF: 13.2±4.6, VNS: 9.3±2.4 pg/mg, p<0.05) and spleen (CHF: 170.2±65, VNS: 115.4±58.8 pg/mg, p<0.05). TNF-α, IL-6, HMGB-1 and CRP remained unchanged. In addition, VNS significantly reduced the expression of TGF-β in LV which is a key mediator of fibroblast activation (CHF: 31±4.0, VNS: 16.6±2.0 %, p<0.01). In LATE, VNS significantly decreased cardiac fibrosis (Masson’s trichrome stain) (CHF: 4.4±0.7, VNS: 2.9±1.1 %, p<0.01), heart weight (CHF: 3.7±0.5, VNS: 3.2±0.5 g/kg, p<0.01) and LVEDP (CHF: 24.2±5.0, VNS: 17.5±7.1 mmHg, p<0.01), suggesting that VNS prevented cardiac remodeling and preserved LV function. Conclusion: VNS significantly decreased the invasion of macrophage, IL-1β and TGF-β production from the beginning of VNS initiation, and resulted in the decrease of cardiac fibrosis and the improvement of cardiac remodeling as well as cardiac function. VNS induced early suppression of the excessive inflammatory response may lead to its late beneficial effects on CHF.

scholarly journals Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto–Kakizaki (GK) rats

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Nattayaporn Apaijai ◽  
Narattaphol Charoenphandhu ◽  
Jitjiroj Ittichaichareon ◽  
Panan Suntornsaratoon ◽  
Nateetip Krishnamra ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Mitochondrial Dynamics ◽  
Sham Operation ◽  
Estrogen Deprivation ◽  
Gk Rats

Both Type 2 diabetes mellitus (T2DM) and estrogen deprivation have been shown to be associated with the development of cardiovascular disease and adverse cardiac remodeling. However, the role of estrogen deprivation on adverse cardiac remodeling in nonobese T2DM rats has not been clearly elucidated. We hypothesized that estrogen-deprivation aggravates adverse cardiac remodeling in Goto–Kakizaki (GK) rats. Wild-type (WT) and GK rats at the age of 9 months old were divided into two subgroups to have either a sham operation (WTS, GKS) or a bilateral ovariectomy (WTO, GKO) (n = 6/subgroup). Four months after the operation, the rats were killed, and the heart was excised rapidly. Metabolic parameters, cardiomyocytes hypertrophy, cardiac fibrosis, and biochemical parameters were determined. GK rats had hyperglycemia with hypoinsulinemia, and estrogen deprivation did not increase the severity of T2DM. Cardiac hypertrophy, cardiac oxidative stress, and phosphor-antinuclear factor κB were higher in WTO and GKS rats than WTS rats, and they markedly increased in GKO rats compared with GKS rats. Furthermore, cardiac fibrosis, transforming growth factor-β, Bax, phosphor-p38, and peroxisome proliferator- activated receptor γ coactivator-1α expression were increased in GKS and GKO rats compared with the lean rats. However, mitochondrial dynamics proteins including dynamin-related protein 1 and mitofusin-2 were not altered by T2DM and estrogen deprivation. Although estrogen deprivation did not aggravate T2DM in GK rats, it increased the severity of cardiac hypertrophy by provoking cardiac inflammation and oxidative stress in nonobese GK rats.

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