scholarly journals Physical Activity and Inhibition of ACE Additively Modulate ACE/ACE-2 Balance in Heart Failure in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Urszula Tyrankiewicz ◽  
Mariola Olkowicz ◽  
Piotr Berkowicz ◽  
Magdalena Jablonska ◽  
Ryszard T. Smolenski ◽  
...  
Keyword(s):  
Physical Activity ◽  
Heart Failure ◽  
Heart Function ◽  
Combined Treatment ◽  
Training Group ◽  
Cardiac Performance ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Ang Ii ◽  
Spontaneous Physical Activity

Angiotensin-converting enzyme inhibition (ACE-I) and physical activity favorably modulate the ACE/ACE-2 balance. However, it is not clear whether physical activity and ACE-I could synergistically modulate ACE/ACE-2 balance in the course of heart failure (HF). Here, we studied the effects of combined spontaneous physical activity and ACE-I–based treatment on angiotensin (Ang) pattern and cardiac function in a mouse model of HF (Tgαq*44). Tgαq*44 mice with advanced HF (at the age of 12 months) were running spontaneously in a running wheel (exercise training group, ExT) and/or were treated with ACE inhibitor (ACE-I, perindopril, 10 mg/kg) for 2 months. Angiotensin profile was characterized by an LC-MS/MS-based method. The cardiac performance was assessed in vivo by MRI. Ang-(1–7)/Ang II ratio in both plasma and the aorta was significantly higher in the combined treatment group than the ACE-I group or ExT alone, suggesting the additive favorable effects on ACE-2/Ang-(1–7) and ACE/Ang II axes’ balance induced by a combination of ACE-I with ExT. The basal cardiac performance did not differ among the experimental groups of Tgαq*44 mice. We demonstrated additive changes in ACE/ACE-2 balance in both plasma and the aorta by spontaneous physical activity and ACE-I treatment in Tgαq*44 mice. However, these changes did not result in an improvement of failing heart function most likely because the disease was at the end-stage. Ang-(1–7)/Ang II balance represents a valuable biochemical end point for monitoring therapeutic intervention outcome in heart failure.

Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure

2021 ◽  
Author(s):  
Jin-Ling Huo ◽  
Lemin Jiao ◽  
Qi An ◽  
Xiuying Chen ◽  
Yuruo Qi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Wild Type Mouse ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Ang Ii

Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

scholarly journals Celastrol Attenuates Angiotensin II–Induced Cardiac Remodeling by Targeting STAT3

2020 ◽  
Vol 126 (8) ◽  
pp. 1007-1023 ◽  
Author(s):  
Shiju Ye ◽  
Wu Luo ◽  
Zia A. Khan ◽  
Gaojun Wu ◽  
Lina Xuan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Heart Function ◽  
Ang Ii ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction

Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

Abstract 131: C-kit+ Cells Generated From Failed Heart Do Not Improve Failed Heart Function

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Liudmila Zakharova ◽  
Hikmet Nural ◽  
James R Nimlos ◽  
Snjezana Popovic ◽  
Lorraine Feehery ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Smooth Muscle Actin ◽  
Functional Improvement ◽  
Gene Expressions ◽  
Coronary Vein ◽  
Mesenchymal Transition

A pilot clinical study using autologous c-Kit+ cells showed improvement in cardiac functions in congestive heart failure (CHF), however, it is unclear if c-Kit+ cells isolated from CHF hearts are equally as potent as cells from controls. To test the potency of CHF c-Kit+ cells, myocardial infarction (MI) was created by permanent ligation of the left anterior descending coronary artery. Six weeks after MI, animals with left ventricle end-diastolic pressure (LVEDP) ≥20 mmHg and scar size ≥30% of left ventricle (LV) were designated as CHF rats. We found that CHF atrial explants generated less c-Kit+ cells compared to shams (15.7% vs. 11% sham vs. CHF). CHF c-Kit+ cells exhibited elevated levels of epicardial to mesenchymal transition markers, including Snail (2.5 fold) and Pai1 (3 fold), while the expression level of epithelial marker, E-cadherin was 3 fold lower in CHF c-Kit+ cells. Moreover, CHF c-Kit+ cells exhibited reduced gene expressions of pluripotency markers; 2.1 fold decrease in Nanog and 4.5 fold decrease in Sox 2 compared to sham cells. To evaluate the potency of the c-Kit+ cells, 1 x 10 6 cells isolated from CHFs or shams were delivered to 3 weeks post-MI CHF hearts. Cells were pre-labeled with GFP to enable their tracing in vivo and delivered to the infarcted myocardium via left coronary vein by a retrograde coronary sinus cell infusion (RCI). RCI delivery resulted in a cell distribution of LV (30%), right atrium (30%) and right ventricle (20%), while only 10% of cells were found in a left atrium. Three weeks after cells delivery, rats transplanted with sham c-Kit+ cells showed improved LVEDP (29.4 ± 6 vs. 11.7 ± 3.5 mmHg, CHF vs. CHF+ sham c-Kit+ cells) and a rise in peak rate of pressure (dPdt max) (3988 ± 520 vs. 5333 ± 597 mmHg/s). In contrast, no functional improvement was detected in rats transplanted with CHF c-Kit+ cells. Histological analysis demonstrated that transplanted c-Kit+/GFP+ cells were mostly incorporated into blood vessels and co-localized with endothelial marker vWf, and α-smooth muscle actin. Our results showed that left coronary vein is an efficient route for c-Kit+ cell delivery and that c-Kit+ cells isolated from CHF rats are less potent when transplanted in chronic heart failure rat model compared to those isolated from control.

Cellular and functional defects in a mouse model of heart failure

2000 ◽  
Vol 279 (6) ◽  
pp. H3101-H3112 ◽  
Author(s):  
Giovanni Esposito ◽  
L. F. Santana ◽  
Keith Dilly ◽  
Jader Dos Santos Cruz ◽  
Lan Mao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Heart Function ◽  
Imaging Techniques ◽  
Single Cells ◽  
Structural Protein ◽  
Muscle Lim Protein ◽  
Intracellular Ca ◽  
Whole Heart

Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP−/−). The character and extent of the heart failure that occurs in MLP−/− mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP−/−mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP−/− mice were examined in isolated single cells using patch-clamp and confocal Ca2+ concentration ([Ca2+]) imaging techniques. This cellular investigation revealed unchanged Ca2+ currents and Ca2+ spark characteristics but decreased intracellular [Ca2+] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP−/− mice that express a cardiac-targeted transgene, which blocks the function of β-adrenergic receptor (β-AR) kinase-1 (βARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP−/− mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the β-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of βARK1 action may prove an effective therapy for heart failure.

scholarly journals Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging

2015 ◽  
Vol 309 (8) ◽  
pp. H1336-H1345 ◽  
Author(s):  
Janet R. Manning ◽  
Catherine N. Withers ◽  
Bryana Levitan ◽  
Jeffrey D. Smith ◽  
Douglas A. Andres ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Calcium Current ◽  
Ventricular Myocytes ◽  
Morphological Changes ◽  
Heart Function ◽  
Early Time ◽  
Cardiac Phenotype ◽  
Systolic And Diastolic Function

Rad-GTPase is a regulator of L-type calcium current (LTCC), with increased calcium current observed in Rad knockout models. While mouse models that result in elevated LTCC have been associated with heart failure, our laboratory and others observe a hypercontractile phenotype with enhanced calcium homeostasis in Rad−/−. It is currently unclear whether this observation represents an early time point in a decompensatory progression towards heart failure or whether Rad loss drives a novel phenotype with stable enhanced function. We test the hypothesis that Rad−/− drives a stable nonfailing hypercontractile phenotype in adult hearts, and we examine compensatory regulation of sarcoplasmic reticulum (SR) loading and protein changes. Heart function was measured in vivo with echocardiography. In vivo heart function was significantly improved in adult Rad−/− hearts compared with wild type. Heart wall dimensions were significantly increased, while heart size was decreased, and cardiac output was not changed. Cardiac function was maintained through 18 mo of age with no decompensation. SR releasable Ca2+ was increased in isolated Rad−/− ventricular myocytes. Higher Ca2+ load was accompanied by sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) protein elevation as determined by immunoblotting and a rightward shift in the thapsigargan inhibitor-response curve. Rad−/− promotes morphological changes accompanied by a stable increase in contractility with aging and preserved cardiac output. The Rad−/− phenotype is marked by enhanced systolic and diastolic function with increased SR uptake, which is consistent with a model that does not progress into heart failure.

scholarly journals Toll-Like Receptor 9 Promotes Cardiac Inflammation and Heart Failure during Polymicrobial Sepsis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Ralph Lohner ◽  
Markus Schwederski ◽  
Carolin Narath ◽  
Johanna Klein ◽  
Georg D. Duerr ◽  
...  
Keyword(s):  
Heart Failure ◽  
Peritoneal Cavity ◽  
Heart Function ◽  
Bacterial Load ◽  
Systolic Pressure ◽  
Polymicrobial Sepsis ◽  
Toll Like Receptor ◽  
Cardiac Inflammation ◽  
Continuous Release

Background. Aim was to elucidate the role of toll-like receptor 9 (TLR9) in cardiac inflammation and septic heart failure in a murine model of polymicrobial sepsis.Methods. Sepsis was induced via colon ascendens stent peritonitis (CASP) in C57BL/6 wild-type (WT) and TLR9-deficient (TLR9-D) mice. Bacterial load in the peritoneal cavity and cardiac expression of inflammatory mediators were determined at 6, 12, 18, 24, and 36 h. Eighteen hours after CASP cardiac function was monitoredin vivo. Sarcomere length of isolated cardiomyocytes was measured at 0.5 to 10 Hz after incubation with heat-inactivated bacteria.Results. CASP led to continuous release of bacteria into the peritoneal cavity, an increase of cytokines, and differential regulation of receptors of innate immunity in the heart. Eighteen hours after CASP WT mice developed septic heart failure characterised by reduction of end-systolic pressure, stroke volume, cardiac output, and parameters of contractility. This coincided with reduced cardiomyocyte sarcomere shortening. TLR9 deficiency resulted in significant reduction of cardiac inflammation and a sustained heart function. This was consistent with reduced mortality in TLR9-D compared to WT mice.Conclusions. In polymicrobial sepsis TLR9 signalling is pivotal to cardiac inflammation and septic heart failure.

scholarly journals Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1053
Author(s):  
Petr Kala ◽  
Matúš Miklovič ◽  
Šárka Jíchová ◽  
Petra Škaroupková ◽  
Zdeňka Vaňourková ◽  
...  
Keyword(s):  
Heart Failure ◽  
Enzyme Inhibitor ◽  
Combined Treatment ◽  
Renin Angiotensin System ◽  
Arachidonic Acid Metabolism ◽  
Epoxyeicosatrienoic Acid ◽  
In Vivo Evaluation ◽  
The Difference ◽  
Final Survival

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.

Impact of exercise training on ventricular properties in a canine model of congestive heart failure

1997 ◽  
Vol 272 (3) ◽  
pp. H1382-H1390 ◽  
Author(s):  
K. Todaka ◽  
J. Wang ◽  
G. H. Yi ◽  
M. Knecht ◽  
R. Stennett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Heart Function ◽  
Systolic Pressure ◽  
Cardiac Pacing ◽  
Left Ventricular ◽  
Lv Function ◽  
Myocardial Stiffness

Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHF(EX), 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2,540 +/- 440 vs. 1,720 +/- 300 mmHg/s, P < 0.05) and LV end-diastolic pressure (9 +/- 5 vs. 19 +/- 4 mmHg, P < 0.05) in CHF(EX) compared with CHFs. The hearts were then isolated and cross perfused for in vitro measurement of isovolumic pressure-volume relations; these results were compared with those of six normal dogs (N). Systolic function was similarly depressed in both groups of pacing animals [end-systolic elastance (Ees) values of 1.66 +/- 0.47 in CHFs, 1.77 +/- 0.38 in CHF(EX), and 3.05 +/- 0.81 mmHg/ml in N, with no changes in volume axis interceptors of the end-systolic pressure-volume relationship]. The diastolic myocardial stiffness constant, k, was elevated in CHFs and was normalized by exercise training (32 +/- 3 in CHFs, 21 +/- 3 in CHF(EX), 20 +/- 4 in N). Thus daily exercise training preserved in vivo hemodynamics during 4 wk of rapid cardiac pacing and was accompanied by a significant change in diastolic myocardial stiffness in vitro. These findings suggest that changes in heart function may contribute to the overall beneficial hemodynamic effects of exercise training in CHF by a significant effect on diastolic properties.

The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure

2001 ◽  
Vol 280 (4) ◽  
pp. H1853-H1860 ◽  
Author(s):  
Che-Ping Cheng ◽  
Tomohiko Ukai ◽  
Katsuya Onishi ◽  
Nobuyuki Ohte ◽  
Makoto Suzuki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Combined Treatment ◽  
Left Ventricular ◽  
Ang Ii ◽  
Systolic Volume ◽  
Minimum Pressure ◽  
Endothelin 1 ◽  
Before And After ◽  
Very High

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1) during Ex may contribute to this response. We assessed the effect of Ex on circulating plasma levels of ANG II and ET-1 and left ventricular (LV) dynamics before and after pacing-induced CHF at rest and during Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (τ), LV end-systolic volume (VES), and LV minimum pressure with a downward shift of the LV early diastolic portion of the pressure-volume (P-V) loop. This produced an increase in peak LV filling rate without an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels during Ex. After CHF, mean LA pressure, τ, and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT1-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.

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