Abstract 13113: Dipeptidyl Peptidase 4 Inhibition Ameliorates Hypertensive Heart Failure via Suppression of Angiotensin-ii-mediated Cardiac Na+/h+ Exchanger1 Pathway

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Haruya Kawase ◽  
Yasuko K Bando ◽  
Morihiko Aoyama ◽  
Akio Monji ◽  
Toko Mitsui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dipeptidyl Peptidase ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Preclinical Models ◽  
Hypertensive Rats ◽  
Lung Weight ◽  
Spontaneously Hypertensive ◽  
Dipeptidyl Peptidase 4 ◽  
Cultured Cardiomyocytes

Introduction: Hypertension is primary cause of heart failure (HF). Several reports demonstrated the blood-pressure (BP)-lowering property of dipeptidyl peptidase 4 (DPP4) inhibitors. Hypothesis: We tested the effect of a new DPP4 inhibitor teneligliptin on BP and HF using preclinical models. Methods: Spontaneously hypertensive rats (SHR; 10 week-old male) and normotensive counterpart (WKY) were treated with TEN (10mg/kg/day) for 4 weeks. Hypertensive HF was evaluated in terms of BP, cardiac function, histological remodeling, and pulmonary congestion. Results: Cardiac catheterization revealed that TEN ameliorated hypertension of SHR-CON (Fig.1). The maximum dP/dt of SHR-CON was elevated (10452±539 for SHR-CON and 5739±599 for WKY-CON), which was reduced by TEN (8033±656 in SHR-TEN) without affecting heart rate. Diastolic indices (minimum dP/dt and tau) were ameliorated by TEN. SHR-CON exhibited increase in heart and body weight (BW) ratio, left ventricular (LV) wall thickness, cardiomyocyte hypertrophy and fibrosis, which were attenuated by TEN. Elevated lung weight and BW ratio and circulating BNP level of SHR-CON were ameliorated by TEN. Cardiac and circulating DPP4 activities of SHR-CON were elevated, which was suppressed by TEN. Vasorelaxant signaling (Akt/eNOS) of each aorta and heart remained unaffected by TEN. Circulating angiotensin-2 (AT-II) was elevated in SHR-CON, which was suppressed by TEN without affecting ACE activity (Fig1). Because DPP4 interacts with Na+/H+ exchanger (NHE)-1 and -3, and NHE1 is related to hypertension and cardiac hypertrophy. In SHR-CON heart, NHE1 expression was elevated (Fig1), which was decreased by TEN. NHE-1 of cultured cardiomyocytes was upregulated by AT-II. Conclusions: TEN ameliorates hypertensive HF via normalizing elevated AT-II through an ACE-independent pathway, leading to reversal of hypertensive cardiac remodeling modulated by pathological AT-II/NHE-1 axis.

Abstract P381: Ecklonia Stolonifera Okamura Extract Suppresses Hypertrophic Responses In Cardiomyocytes And Development Of Heart Failure By Inhibiting P300-HAT Activity

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Takahiro Katagiri ◽  
Yoichi Sunagawa ◽  
Masafumi Funamoto ◽  
Yasufumi Katanasaka ◽  
Yusuke Miyazaki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Transcription ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Cardiomyocyte Hypertrophy ◽  
Cell Diameter ◽  
Mrna Levels ◽  
Ecklonia Stolonifera ◽  
Hypertrophic Response ◽  
Cultured Cardiomyocytes

Introduction: Heart failure is the leading cause of death in the world. Cardiomyocyte hypertrophy is observed during the development of heart failure, suggesting that its inhibition is a potential target for the prevention and treatment of heart failure. In this study, we screened a natural compound library using cultured cardiomyocytes and found that Ecklonia stolonifera Okamura extract (ESE) suppressed cardiomyocyte hypertrophy. ESE, a perennial brown alga, has been reported to have various bioactive effects, such as antioxidant and anti-inflammatory activity, but its effect on heart failure is still unclear. Therefore, we investigated whether ESE has an inhibitory effect on cardiomyocyte hypertrophic response and on the progression of heart failure in post-myocardial infarction (MI) rats. Methods and Results: First, primary cultured cardiomyocytes from neonatal rats were treated with ESE and then stimulated with phenylephrine (PE) for 48 hours. ESE (1000 μg/mL) significantly suppressed PE-induced increases in cardiomyocyte surface area, hypertrophic response gene transcription, and acetylation of histone H3K9. An in vitro p300-HAT assay indicated that ESE directly inhibited p300-HAT activity (IC50: 505 μg/mL). Next, one week after the ligation of the left anterior descending artery, rats with moderate MI (left ventricular fractioning shorting (LVFS) <40%) were randomly assigned to three groups: vehicle (saline) (n=9), ESE (0.3 g/kg) (n=10), or ESE (1 g/kg) (n=10). Daily oral administration was repeated for 8 weeks. After treatment, LVFS was significantly higher in the ESE (1 g/kg) group (23.3 ± 0.7%, p<0.05) than in the vehicle group (16.6 ± 1.3%). Next, the hearts were isolated and histological analysis, evaluation of gene transcription, and measurement of histone H3K9 acetylation. were performed. ESE treatment significantly suppressed MI-induced increases both in myocardial cell diameter and in the mRNA levels of hypertrophic response genes. ESE also inhibited MI-induced perivascular fibrosis and the acetylation of histone H3K9. Conclusion: These results suggest that ESE suppresses both hypertrophic responses in cardiomyocytes and the development of heart failure by inhibiting p300-HAT activity. Further studies are needed to clarify the effectiveness of ESE for heart failure therapy.

Abstract P454: The Interaction Of P300 With Brg1 Acetylated The Histone H3 Globular Domain In Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
sho uehara ◽  
Tatsuya Morimoto
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Globular Domain ◽  
Mrna Levels ◽  
Transcriptional Coactivator ◽  
Post Translational Modifications ◽  
Hypertrophic Response ◽  
Cultured Cardiomyocytes

Background: Epigenetic regulatory mechanisms such as histone post-translational modifications are involved in the development of heart failure. Although the acetylation of tail domains, such as H3K9, has been extensively studied, that of H3K122, the globular domain, has received much less attention. Acetylation of the globular domain directly activates transcription by destabilizing histone-DNA binding. However, the acetylation of these domains during the transition from left ventricular hypertrophy (LVH) to heart failure (HF) remains unknown. Methods and Results: Primary cultured cardiomyocytes prepared from neonatal rats were treated with phenylephrine (PE). PE increased the acetylation of H3K9 and H3K122. The acetylation of H3K9 and H3K122 on the promoters of ANF and BNP, which are hypertrophic reaction genes, was increased in cardiomyocyte hypertrophy. To investigate whether the transcriptional coactivator p300 is involved in the acetylation of H3K9 and H3K122, p300 knockdown was used. p300 knockdown suppressed PE-induced cardiomyocyte hypertrophy and the acetylation of H3K9 and H3K122. In Dahl-salt sensitive rats, in vivo chromatin-immunoprecipitation assays revealed that the acetylation of H3K9 on the promoter of the hypertrophic response genes was significantly increased in LVH, but the acetylation of H3K122 was not increased in LVH. However, H3K122 acetylation was significantly increased in HF. On the other hand, there was no difference in the amount of recruitment of p300 in LVH and HF. Interestingly, immunoprecipitation-WB showed that binding of p300 with BRG1, a key component of the SWI/SNF complex, was enhanced in HF. The recruitment of BRG1 increased significantly in HF compared to LVH. Moreover, PFI-3, a BRG1 inhibitor, significantly suppressed a PE-induced increase in cardiomyocyte surface area, the mRNA levels of ANF and BNP, and the acetylation of H3K9 and H3K122 in cultured cardiomyocytes. Conclusion: This study demonstrates that the acetylation of H3K122 is enhanced via the interaction of p300 and BRG1 in heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.

Haemodynamic and Neurohumoral Changes in Spontaneously Hypertensive Rats with Aortocaval Fistulae

1993 ◽  
Vol 84 (5) ◽  
pp. 531-535 ◽  
Author(s):  
Tamiko Oka ◽  
Hikaru Nishimura ◽  
Masakuni Ueyama ◽  
Jiro Kubota ◽  
Keishiro Kawamura
Keyword(s):  
Heart Failure ◽  
Spontaneously Hypertensive Rats ◽  
Wistar Rats ◽  
Left Ventricular ◽  
Heart Weight ◽  
Stroke Index ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
High Output Heart Failure ◽  
High Output

1. Our aim was to evaluate the effects of an aortocaval fistula (1 mm) on cardiorenal haemodynamics, cardiac hypertrophy and neurohumoral factors in spontaneously hypertensive rats and to compare the results with those observed in Wistar rats at 2 weeks after fistulae placement. Sham-operated spontaneously hypertensive rats and Wistar rats served as controls. 2. Heart weight was significantly increased in spontaneously hypertensive rats (34%) and in Wistar rats (43%) at 2 weeks after fistula creation. Left ventricular systolic pressure and dp/dtmax. were significantly decreased (both P <0.01) in spontaneously hypertensive rats with fistulae which had higher left ventricular end-diastolic pressure than Wistar rats with fistulae (P <0.01). Signs of circulatory congestion (ascites, tachypnoea, prostration) were observed only in the overloaded spontaneously hypertensive rats (45%). Cardiac index was comparably increased in both fistulae groups due to an increase in stroke index, since heart rate was not increased. 3. Fistulae placement decreased renal blood flow and kidney weight, and increased blood urea nitrogen to a greater degree in spontaneously hypertensive rats (all P <0.05); serum creatinine levels were unaltered. Plasma noradrenaline concentration was increased in spontaneously hypertensive rats with fistulae (P <0.05), whereas plasma renin activity was not changed. 4. Thus, spontaneously hypertensive rats with fistulae developed overt haemodynamic signs of high-output heart failure with frequent ascites and dyspnoea, whereas most of these findings were milder or absent in Wistar rats. This model provides an opportunity to evaluate the pathophysiological and pharmacological responses in high-output heart failure.

Impaired myocardial function in spontaneously hypertensive rats with heart failure

1991 ◽  
Vol 260 (1) ◽  
pp. H136-H145 ◽  
Author(s):  
C. H. Conrad ◽  
W. W. Brooks ◽  
K. G. Robinson ◽  
O. H. Bing
Keyword(s):  
Heart Failure ◽  
Muscle Function ◽  
Spontaneously Hypertensive Rats ◽  
Ventricular Hypertrophy ◽  
Myocardial Function ◽  
Left Ventricular ◽  
Hypertensive Rats ◽  
Shortening Velocity ◽  
Tension Development ◽  
Spontaneously Hypertensive

We have observed that many spontaneously hypertensive rats (SHR) between the ages of 18 and 24 mo develop findings suggestive of heart failure, including pleural and pericardial effusions, left atrial thrombi, and right ventricular hypertrophy. Isolated left ventricular papillary muscle function was studied in these animals (SHR-F), in age-matched SHRs without evidence of heart failure (SHR-NF), and in nonhypertensive controls (WKY). Preparations from SHR-F showed depression of active tension development (3.58 +/- 1.75 g/mm2, means +/- SD) compared with both SHR-NF (7.17 +/- 0.94) and WKY (6.17 +/- 1.00) (P less than 0.01). Shortening velocity was also depressed in SHR-F (0.95 +/- 0.38 lengths/s) compared with SHR-NF (1.60 +/- 0.30; P less than 0.05) and WKY groups (2.15 %/- 0.48; P less than 0.01). Depression of muscle function was not found before 18 mo of age. Thus the aging SHR is a model in which one can observe the transition from chronic stable left ventricular hypertrophy to overt heart failure. Furthermore, left ventricular papillary muscles from SHRs with heart failure show evidence of significant contractile dysfunction, suggesting that impairment of intrinsic myocardial function underlies the development of heart failure.

Role of angiotensin-signalling in anthracycline-induced cardiotoxicity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Findlay ◽  
J.H Gill ◽  
R Plummer ◽  
C.J Plummer
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Late Onset ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Funding Source ◽  
Study Results

Abstract   Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

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