scholarly journals HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling

2014 ◽  
Vol 307 (2) ◽  
pp. H252-H258 ◽  
Author(s):  
Kimberly M. Demos-Davies ◽  
Bradley S. Ferguson ◽  
Maria A. Cavasin ◽  
Jennifer H. Mahaffey ◽  
Sarah M. Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Wasting ◽  
Striated Muscle ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.

Abstract 13433: Angiotensin II Type 2 Receptor Regulates Skeletal Myoblast Differentiation: Implications for treatment of Cachexia and Skeletal Muscle Wasting

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tadashi Yoshida ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Regeneration ◽  
Muscle Wasting ◽  
Skeletal Muscle Regeneration ◽  
Myoblast Differentiation ◽  
Muscle Physiology ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II infusion in rodents causes skeletal muscle wasting and decreases muscle regenerative potential via Ang II type 1 receptor (AT1R) signaling, likely contributing to cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology remains unknown. We found that AT2R expression was robustly increased in mouse skeletal myoblasts during differentiation, suggesting that the AT2R plays an important role in skeletal muscle regeneration. To test this hypothesis, we infused mice with AT2R antagonist PD123319 (PD, 30 mg/kg/d) or agonist CGP123319 (CGP, 1 μg/kg/min) during cardiotoxin (CTX)-induced muscle injury and regeneration. PD reduced the size of regenerating myofibers (727.5±54.6 and 516.0±37.0 μm2 in sham and PD, respectively, p<0.05) and expression of the myoblast differentiation markers myogenin and eMyHC (56.9% and 40.2% decrease in PD, respectively. p<0.01), whereas CGP had the opposite effects. siRNA mediated AT2R knockdown in mouse primary myoblasts suppressed the increase of myogenin and desmin, resulting in lowered differentiation. We analyzed changes in phosphoprotein levels in myoblasts after AT2R knockdown by phosphoprotein array and identified multiple changes, including increased phospho-ERK1/2 levels. Importantly, inhibition of ERK1/2 restored normal myoblast differentiation in the setting of AT2R knockdown, suggesting the AT2R positively regulates myoblast differentiation by reducing ERK1/2 activity. Furthermore, we found that skeletal muscle regeneration was reduced (decreased regenerating myofiber size and myogenin/desmin expression) in a mouse myocardial infarction model of CHF, concomitantly with markedly blunted increase of AT2R expression, strongly suggesting that the AT2R plays an important role in the reduction of skeletal muscle function in CHF. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regeneration, providing a new therapeutic target in wasting disorders such as CHF and CKD.

scholarly journals Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle

2019 ◽  
Vol 126 (6) ◽  
pp. 1550-1562 ◽  
Author(s):  
Kleiton Augusto Santos Silva ◽  
Thaysa Ghiarone ◽  
Kathy Schreiber ◽  
DeAna Grant ◽  
Tommi White ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Protein Expression ◽  
Chronic Diseases ◽  
Muscle Wasting ◽  
Beclin 1 ◽  
Ang Ii ◽  
Autophagosome Formation ◽  
Skeletal Muscle Wasting ◽  
And Function

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5′-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.

scholarly journals Central and obstructive apneas prevalence in heart failure with reduced, mid-range and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Borrelli ◽  
P Sciarrone ◽  
F Gentile ◽  
N Ghionzoli ◽  
G Mirizzi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Cardiopulmonary Exercise Testing ◽  
Left Ventricular ◽  
Apnea Hypopnea Index ◽  
Preserved Ejection Fraction ◽  
2D Echocardiography

Abstract Background Central apneas (CA) and obstructive apneas (OA) are highly prevalent in heart failure (HF) both with reduced and preserved systolic function. However, a comprehensive evaluation of apnea prevalence across HF according to ejection fraction (i.e HF with patients with reduced, mid-range and preserved ejection fraction- HFrEf, HFmrEF and HFpEF, respectively) throughout the 24 hours has never been done before. Materials and methods 700 HF patients were prospectively enrolled and then divided according to left ventricular EF (408 HFrEF, 117 HFmrEF, 175 HFpEF). All patients underwent a thorough evaluation including: 2D echocardiography; 24-h Holter-ECG monitoring; cardiopulmonary exercise testing; neuro-hormonal assessment and 24-h cardiorespiratory monitoring. Results In the whole population, prevalence of normal breathing (NB), CA and OA at daytime was 40%, 51%, and 9%, respectively, while at nighttime 15%, 55%, and 30%, respectively. When stratified according to left ventricular EF, CA prevalence decreased from HFrEF to HFmrEF and HFpEF: (daytime CA: 57% vs. 43% vs. 42%, respectively, p=0.001; nighttime CA: 66% vs. 48% vs. 34%, respectively, p&lt;0.0001), while OA prevalence increased (daytime OA: 5% vs. 8% vs. 18%, respectively, p&lt;0.0001; nighttime OA: 20 vs. 29 vs. 53%, respectively, p&lt;0.0001). When assessing moderte-severe apneas, defined with an apnea/hypopnea index &gt;15 events/hour, prevalence of CA was again higher in HFrEF than HFmrEF and HFpEF both at daytime (daytime moderate-severe CA: 28% vs. 19% and 23%, respectively, p&lt;0.05) and at nighttime (nighttime moderate-severe CA: 50% vs. 39% and 28%, respectively, p&lt;0.05). Conversely, moderate-severe OA decreased from HFrEF to HFmrEF to HFpEF both at daytime (daytime moderate-severe OA: 1% vs. 3% and 8%, respectively, p&lt;0.05) and nighttime (noghttime moderate-severe OA: 10% vs. 11% and 30%, respectively, p&lt;0.05). Conclusions Daytime and nighttime apneas, both central and obstructive in nature, are highly prevalent in HF regardless of EF. Across the whole spectrum of HF, CA prevalence increases and OA decreases as left ventricular systolic dysfunction progresses, both during daytime and nighttime. Funding Acknowledgement Type of funding source: None

scholarly journals Loop diuretic use is associated with skeletal muscle wasting in patients with heart failure

2020 ◽  
Vol 76 (1) ◽  
pp. 109-114
Author(s):  
Ippei Nakano ◽  
Masaya Tsuda ◽  
Shintaro Kinugawa ◽  
Arata Fukushima ◽  
Naoya Kakutani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Loop Diuretic ◽  
Skeletal Muscle Wasting ◽  
Patients With Heart Failure

Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction

2001 ◽  
Vol 102 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Suneel TALWAR ◽  
Iain B. SQUIRE ◽  
Russell J. O'BRIEN ◽  
Paul F. DOWNIE ◽  
Joan E. DAVIES ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Clinic Visit ◽  
Left Ventricular ◽  
Lv Function ◽  
Ventricular Remodelling

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.

2371Electrocardiographic features and their echocardiographic correlates in peripartum cardiomyopathy based on the EURObservational registry on PPCM

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A C Mbakwem ◽  
J Bauersachs ◽  
C Viljoen ◽  
P Van Der Meer ◽  
M Petrie ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ethnic Differences ◽  
Regional Differences ◽  
Sinus Tachycardia ◽  
Systolic Function ◽  
Nyha Class ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Peripartum Cardiomyopathy ◽  
Qtc Interval

Abstract Background Cardiac disease remains an important cause of maternal morbidity and mortality globally. Peripartum cardiomyopathy (PPCM), defined as heart failure secondary to left ventricular (LV) systolic dysfunction in previously healthy women towards the end of pregnancy or up to five months following delivery, can result in cardiogenic shock due to severe LV dysfunction or arrhythmias leading to sudden cardiac death. Cardiac electrical activity and its relationship to cardiac dysfunction have not yet been interrogated in large multi-centre studies. Purpose This study aimed to identify the ECG abnormalities associated with PPCM; their relationship with echocardiographic structural and functional abnormalities and explore regional and ethnic differences in ECG features. Methods We included the first 411 patients enrolled into the EURObservational PPCM registry (EORP). Baseline demographic, clinical and echocardiographic data were collected. ECGs were analysed for rate; rhythm; QRS width, axis and morphology; and QTc interval. Results Mean age of the women (from >40 countries) was 30.7±6.4 years. More than two thirds of patients presented with NYHA class III or IV (with no regional differences). The median QRS rate was 102bpm (IQR 87–117). More than half presented with sinus tachycardia (QRS rate >100bpm), whereas atrial fibrillation was rare (2.27%). The mean QRS width was 90.1ms ±21.5, with regional differences (ESC 93.8ms ±21.7 vs. non-ESC 86.8ms ±20.8, P<0.001). Left bundle branch block (LBBB) was reported in 9.30% with no regional or ethnic differences. Left ventricular hypertrophy (LVH) was present in a quarter of the cohort, and more prevalent amongst African (59.62%) and Asian (23.17%) than Caucasians (7.63%, P<0.001). The median QTc by Bazett was 456.7ms (IQR 409–490.7) and almost half (47.11%) had prolonged QTc (>460ms). The median LVEDD was 60mm (IQR 55–65) on echocardiography. Compared with their Asian and Caucasian counterparts, African patients were more likely to have LV dilatation (LVEDD>53mm: 70.11%, 79.31% and 89.42% respectively; P=0.004). The median LV ejection fraction (LVEF) was 32.50% (IQR 25–39) with no significant regional or ethnic differences. Sinus tachycardia predicted poor systolic function (OR 1.85 [95% CI 1.20–2.85], p=0.006). LVEF <35% was associated with a significantly higher QRS rate (median rate 107 vs. 98bpm, p=0.002). Women with LVEDD ≥53mm had a longer mean QRS duration (92.0±22.4 vs. 82.4±15.4ms, p<0.001) and frequency of LBBB (11.15% vs 1.54%, p=0.016). LBBB was a predictor of LVEDD >53mm (sensitivity 11.15%; specificity 98.46%; PPV 97.14%; NPV 19.10%; OR 8.02 [95% CI 1.08–59.66], p=0.042). Conclusion Patients with PPCM commonly present with sinus tachycardia, LVH, and/or prolonged QTc interval on their ECG. Wide QRS and/or LBBB, were associated with LVEDD>53mm. Sinus tachycardia, however, was associated with LVEF<35%. Risk of arrhythmia in those with prolonged QTc remains to be ascertained. Acknowledgement/Funding Heart Failure Association of the ESC

Sign in / Sign up

Export Citation Format

Share Document