Abstract 393: Chronic Nebivolol Treatment Attenuates MMP Activity and Oxidative Stress and Improves Renovascular Hypertension-induced Cardiac Hypertrophy

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Elen R Sanchez ◽  
Carla S Ceron ◽  
Danielle A Gimaraes ◽  
Cibele M Prado ◽  
Alisson Martins-Oliveira ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Structural Changes ◽  
Sham Group ◽  
Antioxidant Properties ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Left Renal Artery ◽  
Similar Reduction ◽  
Lv Remodeling ◽  
Antioxidant Effects

Nebivolol (Nebi) is the most selective cardiac β1-adrenergic receptor blocker and exerts antioxidant effects. Reactive oxygen species (ROS) enhance cardiac matrix metalloproteinase activity (MMPs) and contribute to hypertension-induced left ventricular hypertrophy (LVH). However, it is uncertain whether Nebi decreases MMP-2 levels and cardiac remodeling associated with hypertension as a result of its antioxidant properties. Hypertension was induced by clipping the left renal artery (2K1C). Six weeks after surgery, hypertensive and sham rats were treated with Nebi, Metoprolol (Meto) or Vehicle (by gavage) for four weeks. Systolic blood pressure (SBP) was monitored weekly by tail-cuff plethysmography. LV structural changes were studied in hematoxylin/eosin sections. MMP levels and activity were determined by immunofluorescence and in situ zymography. ROS and nitrotyrosine levels were evaluated by dihydroethidium and immunohistochemistry, respectively. Similar reduction in SBP was found with both treatments (202±5 mmHg in 2K1C+Vehicle versus 161±19 and 162±18 mmHg in 2K1C Nebi or Meto groups, respectively; P<0.05). Both treatments reduced LV remodeling and ROS formation (P<0.05). Both drugs decreased nitrotyrosine levels (3.9±0.2, 2.3±0.3, and 2.4±0.3 arbitrary units, respectively in 2K1C+vehicle, 2K1C+Meto, and 2K1C+Nebi groups, respectively; P<0.05). Increased MMP-2 levels (16.0±2.0 versus 7.0±0.9 arbitrary units; P<0.05) and activity (8.0±0.4 versus 6.0±0.1 arbitrary units; P<0.05) were observed in the 2K1C+vehicle group when compared to the sham group. These alterations were normalized by both treatments (similar levels to those found in the sham group). No significant changes were observed in the sham groups. These findings suggest that different β-blockers exert important antioxidant effects that may underlie the lower LV MMP activity and cardiac remodeling in 2K1C hypertension.

Abstract 1770: Proteasome Switching is Associated with Adverse Cardiac Remodeling in a Transgenic Mouse Model of Sustained Inflammatory Signaling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei Wang ◽  
Gabor Szalai ◽  
Natarajan Sivasubramanian ◽  
Douglas L Mann
Keyword(s):  
Proteolytic Activity ◽  
Cardiac Remodeling ◽  
Fold Increase ◽  
Left Ventricular ◽  
26S Proteasome ◽  
Myocardial Inflammation ◽  
Fluorescent Substrate ◽  
Lv Remodeling ◽  
Apoptotic Proteins

The 26S proteasome possess proteolytic activity and deubiquitinating (DUB) activity of ubiquitin tagged proteins. Whereas the proteolytic activity of the 26S proteasome facilitates protein degradation, proteasome DUB activity spares proteins from degradation by shortening the length of the ubiquitin chains, thereby preventing proteins from being degraded by the 26S proteasome. In yeast, increased DUB activity is beneficial by preventing depletion of ubiquitin pools critical for cell signaling. However, the role of DUB activity in mammalian systems is not known. We have shown that mice with cardiac restricted overexpression of tumor necrosis factor (sTNF mice) develop a heart failure phenotype characterized by progressive left ventricular (LV) remodeling and accumulation of pro-apoptotic proteins, including Smac/Diablo. To determine whether the adverse LV remodeling in sTNF mice was related to alterations in DUB activity we measured the cleavage of ubiquitin-AMC, an in vitro fluorescent substrate for DUBs, in purified preparations of the 26S proteasome obtained from hearts of 4 week old sTNF and littermate (LM) control mice. Compared to LM controls we observed a significant (p < 0.001) 60.8% decrease in activity of the 26S proteasome and a significant (p < 0.01) 24.2% increase in DUB activity in sTNF mouse hearts. There was also a significant (p < 0.01) 11-fold increase myocardial protein levels of USP14, a critical DUB associated with the 26S proteasome in sTNF mouse hearts. The decrease in 26S proteasome activity and increased DUB activity in sTNF mouse hearts was accompanied by an increase in myocardial levels of ubiquitinated SMAC/Diablo. Taken together these results show for the first time that sustained myocardial inflammation leads to switch in the function of the proteasome from a proteolytic function to a protein sparing function. Although this “proteasome switching” may provide a short-term adaptive benefit by preventing depletion of critical ubiquitin pools, it may lead to long-term maladaptive consequences by allowing the progressive accumulation of potentially harmful pro-apoptotic proteins in the cytosol, which may in turn promote programmed cell death and adverse cardiac remodeling.

scholarly journals Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Melka ◽  
A Helbert ◽  
L Lesage ◽  
K Moreau ◽  
K Romariz ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Ejection Fraction ◽  
Ventricular Arrhythmia ◽  
Ventricular Arrhythmias ◽  
Sham Group ◽  
Pig Model ◽  
Vehicle Group ◽  
Electrical Remodeling ◽  
Reduced Ejection Fraction ◽  
Lv Remodeling

Abstract Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF&lt;50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p&lt;0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p&lt;0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p&lt;0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular & Metabolic Diseases Center for Therapeutic Innovation Table 1

Interstitial purine metabolites in hearts with LV remodeling

2004 ◽  
Vol 286 (2) ◽  
pp. H677-H684 ◽  
Author(s):  
Andrey V. Gourine ◽  
Qingsong Hu ◽  
Paul R. Sander ◽  
Aleksandr I. Kuzmin ◽  
Nadia Hanafy ◽  
...  
Keyword(s):  
Uric Acid ◽  
Sham Group ◽  
Adenine Nucleotide ◽  
Left Ventricular ◽  
Atp Depletion ◽  
Sham Operation ◽  
Adrenergic Stimulation ◽  
Purine Metabolites ◽  
Lv Remodeling ◽  
Adenine Nucleotide Pool

The myocardial ATP concentration is significantly decreased in failing hearts, which may be related to the progressive loss of the myocardial total adenine nucleotide pool. The total myocardial interstitial purine metabolites (IPM) in the dialysate of interstitial fluid could reflect the tissue ATP depletion. In rats, postmyocardial infarction (MI) left ventricular (LV) remodeling was induced by ligation of the coronary artery. Cardiac microdialysis was employed to assess changes of IPM in response to graded β-adrenergic stimulation with isoproterenol (Iso) in myocardium of hearts with post-MI LV remodeling (MI group) or hearts with sham operation (sham group). The dialysate samples were analyzed for adenosine, inosine, hypoxanthine, xanthine, and uric acid. LV volume was greater in the MI group (2.2 ± 0.2 ml/kg) compared with the sham group (1.3 ± 0.2 ml/kg, P < 0.05). Infarct size was 28 ± 4%. The baseline dialysate level of uric acid was higher in the MI group (18.9 ± 3.4 μmol) compared with the sham group (4.6 ± 0.7 μmol, P < 0.01). During and after Iso infusion, the dialysate levels of adenosine, xanthine, and uric acid were all significantly higher in the MI group. Thus the level of IPM is increased in hearts with postinfarction LV remodeling both at baseline and during Iso infusion. These results suggest that the decreased myocardial ATP level in hearts with post-MI LV remodeling may be caused by the chronic depletion of the total adenine nucleotide pool.

scholarly journals Features of cardiac remodeling in patients with hypertension of different ethnic groups

2016 ◽  
Vol 13 (2) ◽  
pp. 28-32
Author(s):  
E A Abramov ◽  
V A Nevzorova ◽  
N I Repina
Keyword(s):  
Ethnic Groups ◽  
Cardiac Remodeling ◽  
Ventricular Hypertrophy ◽  
Structural Characteristics ◽  
Left Ventricular ◽  
Hypertensive Patients ◽  
Concentric Left Ventricular Hypertrophy ◽  
Lv Remodeling ◽  
Different Types ◽  
Doppler Analysis

Objective. To study the features of different types of left ventricles (LV) geometry in patients with essential hypertension (EH) of different ethnic groups. Materials and methods. We examined 180 patients, residents of the Sakhalin Region, with 1-3 degree arterial hypertension, including 88 patients of Korean ethnicity aged from 45 to 63 years (mean age - 59.2±0.86 years) and 92 patients of Slavic ethnicity in age from 43 to 64 years (mean age - 58.2±0.93 years). LV structural and functional characteristics were studied by means of echocardiography with Doppler analysis on the ultrasonic system Acuson X300 (HP, USA). Results. The results of assessment of different types of LV geometry revealed the following differences: prevalence of the LV concentric remodeling was higher in patients with EH of Korean ethnicity (21.5% versus 13% among the Slavs, p=0.04). Conclusion. The study of the structural characteristics of left ventricular in patients with hypertension, residents of the Sakhalin Region, revealed that concentric remodeling and concentric left ventricular hypertrophy are the main types of LV geometry in hypertensive patients of both ethnic groups. However, concentric LV remodeling was more often detected in patients with hypertension of Korean ethnicity.

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 Mechanical work and energetic analysis of eccentric cardiac remodeling in a volume overload heart failure in rats

2009 ◽  
Vol 296 (4) ◽  
pp. H1117-H1124 ◽  
Author(s):  
Yoshiaki Takewa ◽  
Elie R. Chemaly ◽  
Miyako Takaki ◽  
Li Fan Liang ◽  
Hongwei Jin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Sham Group ◽  
Group Versus ◽  
Volume Overload ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Energy Utilization ◽  
Male Rats ◽  
Sham Operation

Eccentric cardiac remodeling seen in dilated cardiomyopathy or regurgitant valvular disease is a well-known process of heart failure progression, but its mechanoenergetic profile has not been yet established. We made a volume overload (VO) heart failure model in rats and for the first time investigated left ventricular (LV) mechanical work and energetics in cross-circulated whole heart preparations. Laparotomy was performed in 14 Wistar male rats, and abdominal aortic-inferior vena caval shunt was created in seven rats (VO group). Another seven rats underwent a sham operation without functional shunt (Sham group). LV dimensions changes were followed with weekly transthoracic echocardiography. Three months after surgery, we measured LV pressure and volume and myocardial O2 consumption in isolated heart cross circulation. LV internal dimensions in both systolic and diastolic phases were significantly increased in the VO group versus the Sham group ( P < 0.05). LV pressure was markedly decreased in the VO group versus in the Sham group ( P < 0.05). LV end-systolic pressure-volume relation shifted downward, and myocardial O2 consumption related to Ca2+ handling significantly decreased. The contractile response to Ca2+ infusion was attenuated. Nevertheless, the increase in Ca2+ handling-related O2 consumption per unit change in LV contractility in the VO group was significantly higher than that in the Sham group ( P < 0.05). The levels of sarco(endo)plasmic reticulum Ca2+-ATPase 2a protein were reduced in the VO group ( P < 0.01). In conclusion, VO failing rat hearts had a character of marked contractile dysfunction accompanied with less efficient energy utilization in the Ca2+ handling processes. These results suggest that restoring Ca2+ handling in excitation-contraction coupling would improve the contractility of the myocardium after eccentric cardiac remodeling.

scholarly journals Hemodynamic and Non-Hemodynamic Components of Cardiac Remodeling in Primary Aldosteronism

2021 ◽  
Vol 12 ◽  
Author(s):  
Chien-Ting Pan ◽  
Xue-Ming Wu ◽  
Cheng-Hsuan Tsai ◽  
Yi-Yao Chang ◽  
Zheng-Wei Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Multivariate Analysis ◽  
Cardiac Remodeling ◽  
Primary Aldosteronism ◽  
Left Ventricular Mass Index ◽  
Left Ventricular ◽  
Plasma Aldosterone Concentration ◽  
Lv Remodeling ◽  
Aldosterone Producing Adenoma ◽  
Aldosterone To Renin Ratio

ObjectivesPatients with primary aldosteronism (PA) have cardiac remodeling due to hemodynamic and non-hemodynamic causes. However, component analysis of cardiac remodeling and reversal in PA patients is lacking. We investigated components of cardiac remodeling and reversal after adrenalectomy in patients with aldosterone-producing adenoma (APA).MethodsThis study prospectively enrolled 304 APA patients who received adrenalectomy and 271 with essential hypertension (EH). Clinical, biochemical and echocardiographic data were collected in both groups and 1 year after surgery in the APA patients. The hemodynamic and non-hemodynamic components of left ventricular (LV) remodeling were represented by predicted left ventricular mass index (LVMI) (pLVMI) and inappropriately excessive LVMI (ieLVMI, defined as LVMI-pLVMI).ResultsAfter propensity score matching, 213 APA and 213 EH patients were selected. APA patients had higher hemodynamic (pLVMI) and non-hemodynamic (ieLVMI) components of LV remodeling than EH patients. In multivariate analysis, baseline pLVMI was correlated with systolic blood pressure (SBP) and serum potassium, whereas ieLVMI was correlated with log plasma aldosterone concentration but not blood pressure. Post-operative echocardiography was available in 207 patents and showed significant decreases in both pLVMI and ieLVMI after adrenalectomy. In multivariate analysis, ΔpLVMI was correlated with SBP, ΔSBP, and pre-operative pLVMI, whereas ΔieLVMI was correlated with Δlog aldosterone-to-renin ratio (ARR) and pre-operative ieLVMI.ConclusionsThis study concluded that extensive cardiac remodeling in APA patients occurs through hemodynamic and non-hemodynamic causes. Adrenalectomy can improve both hemodynamic and non-hemodynamic components of LV remodeling. Regressions of pLVMI and ieLVMI were correlated with decreases in blood pressure and ARR, respectively.

Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

2007 ◽  
Vol 292 (1) ◽  
pp. H530-H538 ◽  
Author(s):  
Yasuyuki Onai ◽  
Jun-ichi Suzuki ◽  
Yasuhiro Maejima ◽  
Go Haraguchi ◽  
Susumu Muto ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Treated Group ◽  
Transforming Growth Factor Β1 ◽  
Left Ventricular ◽  
Monocyte Chemoattractant Protein 1 ◽  
Lv Remodeling

Several studies have demonstrated that NF-κB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-κB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IκB that acts via inhibition of IKK-β, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group ( P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 ± 3.57 mm2; IMD-0354, 55.00 ± 3.73 mm2; P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 ± 0.26; IMD-0354, 2.61 ± 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 ± 14.87 pg/ml; IMD-0354, 110.75 ± 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-β1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-κB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.

scholarly journals LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Po-Cheng Chang ◽  
Shien-Fong Lin ◽  
Yen Chu ◽  
Hung-Ta Wo ◽  
Hui-Ling Lee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Western Blot ◽  
Sham Group ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Vehicle Group ◽  
Sham Operation ◽  
Channel Proteins ◽  
Enalapril Therapy

Background. LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods. We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results. The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion. As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

scholarly journals Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

2012 ◽  
Vol 302 (10) ◽  
pp. H2112-H2121 ◽  
Author(s):  
Longhu Li ◽  
Husnain Kh. Haider ◽  
Linlin Wang ◽  
Gang Lu ◽  
Muhammad Ashraf
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Short Hairpin Rna ◽  
Pharmacological Intervention ◽  
Hairpin Rna ◽  
Infarction Size ◽  
Lv Remodeling ◽  
Short Hairpin

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.

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