Abstract P326: Nicotinamide Riboside Kinase-2 Deficiency Promotes Pressure Overload- Induced Dilated Cardiomyopathy And Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Syeda K Shahzadi ◽  
Rizwan Qaisar ◽  
Firdos Ahmad
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Nicotinamide Riboside ◽  
Genetic Ablation ◽  
Jnk Activation

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with a poor prognosis. Nicotinamide riboside kinase-2 (NRK-2), a muscle-specific β1 integrin-binding protein, is predominantly expressed in skeletal muscle and upregulates in several heart failure models. Emerging pieces of evidence suggest that NRK-2 plays a key role in cardiac pathogenesis, however, its role in chronic pressure overload (PO)-induced cardiac remodeling is largely unknown. To investigate the potential role of NRK-2 in PO-induced DCM and delineate the underlying molecular mechanisms, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant LV chamber dilatation [LVIDd(mm); 5.32±0.36 vs. 4.75±0.39, P =0.001] and functional deterioration [LVEF(%); 20.53±8.81vs. 31.2±7.0, P =0.003] during the maladaptive cardiac remodeling phase (6 week). Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing AC16 cardiomyocytes displayed significantly attenuated fetal genes expression and, NRK-2 further suppressed the fetal gene expression when challenged with angiotensin II. Consistently, NRK-2 overexpression attenuated angiotensin II-induced cardiomyocyte death. Mechanistically, NRK-2 was identified as a critical regulator of JNK MAP kinase and NRK-2 overexpression markedly suppressed the angiotensin II-induced JNK activation. Overall, our results demonstrate that NRK-2 regulates dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation.

scholarly journals Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

2021 ◽  
Author(s):  
Syeda Kiran Shahzadi ◽  
Rizwan Qaisar ◽  
Firdos Ahmad
Keyword(s):  
Angiotensin Ii ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Nicotinamide Riboside ◽  
Genetic Ablation ◽  
Human Cardiomyocytes ◽  
Jnk Activation

Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II- induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a critical regulator of JNK MAP kinase where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II- induced JNK activation. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload- induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation.

Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shungo Hikoso ◽  
Kinya Otsu ◽  
Osamu Yamaguchi ◽  
Toshihiro Takeda ◽  
Masayuki Taniike ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Iκb Kinase ◽  
Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

Abstract P478: Farnesyl Transferase Inhibitor Tipifarnib Reduces Circulating Exosomes And Protects Against Pressure Overload-mediated Cardiac Hypertrophy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Vandana Mallaredy
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitor

Clinically, Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the major initiating factors for the onset of cardiac remodeling leading to heart failure. Studies have revealed that HCM characterized by left ventricular hypertrophy, hypercontractility, and impaired relaxation is mainly driven by an intricate crosstalk among the multiple cellular and molecular mechanisms, which leads to heart failure. In agreement with this observation, we investigated if the Tipifarnib-mediated reduction/alteration of circulating exosomes mediates cardiac cell communication during HCM. Several studies have shown Tipifarnib as a potential Farnesyl transferase inhibitor. However, in recent past Tipifarnib has been shown to target exosomes biogenesis by several mechanisms such as inhibiting Ras pathway, ESCRT complex etc. Tipifarnib treatment in mice significantly reduced the number of circulating plasma exosomes. We examined the response of Tipifarnib treatment (10 mg/kg body weight) in C57BL6J male mice subjected to transverse aortic constriction (TAC) surgery. Untreated TAC mice had worsening of systolic Left Ventricular function at 4 weeks that further deteriorated at 8 weeks, while the treatment with Tipifarnib substantially improved cardiac functions by reducing cardiac hypertrophy and fibrosis. Exosomes isolated from the serum of sham and TAC mice with or without tipifarnib were used for in vitro cell based analyses. We observed that the exosomes isolated from Tipifarnib treated TAC mice reduced isoproterenol (ISO)-induced cardiomyoblast hypertrophy and fibrosis-associated genes in adult cardiac fibroblasts. Taken together, our studies suggest Tipifarnib protects against pressure overload induced cardiac remodeling and dysfunction by altering hypertrophic and fibrotic gene expression, by potentially reducing circulating exosomes or by altering exosome contents. Ongoing studies will clarify the molecular mechanisms of these observations.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

P4996The adult heart requires baseline expression of the transcription factor Hand2 to withstand right ventricular pressure overload

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A M C Koop ◽  
R F Videira ◽  
L Ottaviani ◽  
E M Poels ◽  
K W Van De Kolk ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Right Ventricular ◽  
Rna Sequencing ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Adult Heart ◽  
Hypertrophic Growth

Abstract Introduction Heart and neural crest derivatives expressed-2 (Hand2) has been identified as an important embryonic basic helix-loop-helix-transcription factor, with different functions in the development of the first and second heart field, from which the left and right ventricle originate, respectively. Our previous work revealed that Hand2, under conditions of left ventricular (LV) pressure overload, is re-expressed in the adult heart and activates a “fetal gene” program contributing to pathological cardiac remodeling. Ablation of cardiac expression of Hand2 resulted in protection to cardiac stress and attenuated maladaptive remodeling. Purpose In this study, we aimed at unraveling the role of Hand2 during cardiac remodeling in response to right ventricular (RV) pressure overload induced by pulmonary artery banding (PAB). Methods Hand2F/F and MCM− Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic and MRI derived hemodynamic parameters, and molecular remodelling were assessed for experimental groups and compared to sham-operated controls (Fig. 1a). RNA sequencing and gene ontology enrichment analysis were performed to compare the dysregulated genes between the pressure overloaded RV of the control and Hand2 knockout mice. Results After six weeks of increased pressure load (Fig. 1b), levels of Hand2 increased in the control banded animals but, as expected, remained absent in the knockout hearts (Fig. 1c). In contrast to the what was previously observed for the pressure overloaded LV, in the pressure loaded RV, Hand2 depletion resulted in more severe remodelling and dysfunction as reflected by increased hypertrophic growth, increased RV end-diastolic and end-systolic volumes as well as decreased RV ejection fraction (Fig. 1d–g). In addition, RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. These include components of the extracellular matrix structure, collagen assembly and organization and several types of collagens. Genes associated with inflammation response, adhesion and muscle organization were also affected in the RV of the Hand2 KO mice (Fig. 1h). Figure 1 Conclusion Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV, in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.

scholarly journals Dapagliflozin: a Sodium-glucose Cotransporter 2 Inhibitor, Attenuates Angiotensin II-induced Cardiac Fibrotic Remodeling by Regulating TGFβ1/ Smad Signaling

2021 ◽  
Author(s):  
Yuze Zhang ◽  
Xiaoyan Lin ◽  
Yong Chu ◽  
Xiaoming Chen ◽  
Heng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Ang Ii ◽  
Smad Signaling ◽  
Sd Rats ◽  
Sodium Glucose Cotransporter ◽  
Tgf Β1

Abstract Background:Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms.Methods:Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II with or without the indicated concentration of DAPA. The protein levels of collagen and TGF-β1/Smad signaling were measured along with body weight, and blood biochemical indexes.Results:DAPA treatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA treatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-β1/Smads signaling.Conclusion:DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-β1/Smad signaling in a glucose-independent manner. DAPA may serve as a novel therapy for pathological cardiac remodeling.

scholarly journals Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shengqi Huo ◽  
Wei Shi ◽  
Haiyan Ma ◽  
Dan Yan ◽  
Pengcheng Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Protein Expression ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stat3 Signaling ◽  
H9c2 Myoblasts ◽  
And Oxidative Stress ◽  
Stat3 Inhibition

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6 , respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

scholarly journals miR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Que Wang ◽  
Xiaoxue Yu ◽  
Lin Dou ◽  
Xiuqing Huang ◽  
Kaiyi Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Remodeling ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Left Ventricular Myocardium ◽  
Chronic Hypertension ◽  
Arylsulfatase B

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3′-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.

scholarly journals Hyperoside Protects Against Pressure Overload-Induced Cardiac Remodeling via the AKT Signaling Pathway

2018 ◽  
Vol 51 (2) ◽  
pp. 827-841 ◽  
Author(s):  
Xiaofang Wang ◽  
Yuan Liu ◽  
Lili Xiao ◽  
Ling Li ◽  
Xiaoyan Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Akt Signaling ◽  
Neonatal Rat ◽  
Control Group ◽  
Akt Signaling Pathway

Background/Aims: Cardiac hypertrophy is a major predisposing factor for heart failure and sudden cardiac death. Hyperoside (Hyp), a flavonoid isolated from Rhododendron ponticum L., is a primary component of Chinese traditional patent medicines. Numerous studies have shown that Hyp exerts marked anti-viral, anti-inflammatory, anti-oxidant, anti-cancer, anti-ischemic, and particularly cardio-protective effects. However, the effects of Hyp on cardiac hypertrophy have not been explored. The aims of this study were to determine whether Hyp could protect against cardiac remodeling and to clarify the potential molecular mechanisms. Methods: Neonatal rat cardiac myocytes were isolated and treated with different concentrations of Hyp, then cultured with angiotensin II for 48 h. Mice were subjected to either aortic banding or sham surgery (control group). One week after surgery, the mice were treated with Hyp (20 mg/kg/day) or vehicle by oral gavage for 7 weeks. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histology, and biomarkers. Results: Hyp pretreatment suppressed angiotensin II-induced hypertrophy in cardiomyocytes. Hyp exerted no basal effects but attenuated cardiac hypertrophy and dysfunction, fibrosis, inflammation, and oxidative stress induced by pressure overload. Both in vivo and in vitro experiments demonstrated that the effect of Hyp on cardiac hypertrophy was mediated by blocking activation of the AKT signaling pathway. Conclusion: Hyp improves cardiac function and prevents the development of cardiac hypertrophy via AKT signaling. Our results suggest a protective effect of Hyp on pressure overload-induced cardiac remodeling. Taken together, Hyp may have a role in the pharmacological therapy of cardiac hypertrophy.

scholarly journals Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Julius Bogomolovas ◽  
Kathrin Brohm ◽  
Jelena Čelutkienė ◽  
Giedrė Balčiūnaitė ◽  
Daiva Bironaitė ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Expression Patterns ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Expression Levels ◽  
Potential Marker ◽  
End Stage

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1,ANKRD2,TRIM63,TRIM55,NBR1,MLP,FHL2, andTCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevatedANKRD1expression levels marked transition from NYHA < IV to NYHA IV.ANKRD1expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardialANKRD1and serum adiponectin correlated with lowBAX/BCL-2ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM.ANKRD1expression correlated with reduced cardiac contractility and compliance. The association ofANKRD1with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.

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