scholarly journals Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1776
Author(s):  
Beáta Bódi ◽  
Árpád Kovács ◽  
Hajnalka Gulyás ◽  
Lilla Mártha ◽  
Attila Tóth ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Troponin I ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Male Rats ◽  
Diabetic Rat ◽  
Rat Hearts ◽  
Zdf Rats ◽  
Left And Right

Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50 values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function.

Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chengxue Qin ◽  
Rochelle S S Sleaby ◽  
Lea M Delbridge ◽  
Amy J Davidoff ◽  
John C Chatham ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Male Rats ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Cardiac Phenotype ◽  
Rat Hearts ◽  
The Impact

Metabolism of excess glucose is an important component of the aetiology of type 1 diabetes. The cardiac phenotype includes left ventricular (LV) remodelling and LV dysfunction. Increased hexosamine biosythesis (HBP) and downstream upregulation of protein O-GlcNAcylation has been linked to diabetic complications in many organs. Its impact on LV contractile responsiveness is however not well understood. This study aimed to test the hypothesis that acute inhibition of O-GlcNAc signaling protects inotropic responsiveness in type 1 diabetic heart. Hearts isolated from adult Sprague-Dawley male rats were Langendorff-perfused (constant flow, 10ml/min). Baseline and phenylephrine-stimulated (PE, 10μmol/L) LV function was determined in diabetic (8wks post-streptozotocin diabetes, 55mg/kg i.v.) versus non-diabetic sham rats in the presence of pharmacological inhibitors of HBP/O-GlcNAc including 6-diazo-5-oxo-L-norleucine (DON, 20μM) and alloxan (5mM). Diabetic rats exhibited a marked reduction in inotropic responsiveness to PE (Table, mean±SEM, one-way ANOVA, #P<0.05 vs non-diabetic vehicle rats, *P<0.05 vs diabetic vehicle, at 40 mins). Acute interruption of cardiac HBP/O-GlcNAc by DON and Alloxan significantly rescued LV responsiveness to PE in type 1 diabetic rat hearts. These results support further assessment of the impact of upregulated protein O-GlcNAcylation on LV function, particularly in the diabetic heart. Treatment strategies that target HBP may provide significant benefits alone or in combination with current standard treatments, to reduce progression of heart failure and death in type 1 diabetic patients.

Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia

2004 ◽  
Vol 286 (2) ◽  
pp. H545-H551 ◽  
Author(s):  
Joerg Forkel ◽  
Xiaochao Chen ◽  
Susanne Wandinger ◽  
Florian Keser ◽  
Alexey Duschin ◽  
...  
Keyword(s):  
Protein Expression ◽  
Left Ventricular Function ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Right Ventricular Function ◽  
Chronic Hypoxia ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Left And Right

Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O2) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1α and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 ± 6% and 67 ± 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 ± 2% of baseline in Hypo vs. 67 ± 3% in Norm ( P < 0.05). Improved postischemic right ventricular function in Hypo (93 ± 2% and 96 ± 2% of baseline) was observed with 95% O2 or 21% O2 in the perfusate, and it was not attenuated by glibenclamide (5 and 10 μmol/l) (86 ± 4% and 106 ± 6% recovery). HIF-1α mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K+ channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts.

Left Ventricular Mechanics and Myocardial Blood Flow Following Restoration of Normal Activation Sequence in Paced Patients With Long-term Right Ventricular Apical Stimulation

CHEST Journal ◽  
2003 ◽  
Vol 124 (1) ◽  
pp. 233-241 ◽  
Author(s):  
Emmanuel N. Simantirakis ◽  
George E. Kochiadakis ◽  
Konstantinos E. Vardakis ◽  
Nikolaos E. Igoumenidis ◽  
Stavros I. Chrysostomakis ◽  
...  
Keyword(s):  
Blood Flow ◽  
Myocardial Blood Flow ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Ventricular Mechanics ◽  
Left Ventricular Mechanics ◽  
Activation Sequence

Regulation of β myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium

1993 ◽  
Vol 84 (1) ◽  
pp. 61-67 ◽  
Author(s):  
N. K. Green ◽  
M. D. Gammage ◽  
J. A. Franklyn ◽  
A. M. Heagerty ◽  
M. C. Sheppard
Keyword(s):  
Thyroid Hormone ◽  
Right Ventricular ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Transcriptional Level ◽  
Messenger Rnas ◽  
Hypertrophic Response ◽  
Left And Right

1. In order to investigate the molecular mechanisms determining the hypertrophic response of the ventricular myocardium to thyroid hormone administration, changes in left and right ventricular expression of the c-myc, c-fos and H-ras proto-oncogenes in response to treatment with 3,3′,5-tri-iodothyronine were defined. 2. Adult female Wistar rats were treated with daily subcutaneous injections of 3,3′,5-tri-iodothyronine (50 μg) for 1, 3, 7 or 14 days (n = 6 in each treatment group) and the results from 3,3′,5-tri-iodothyronine-treated animals were compared with those obtained from untreated controls (n = 6). Changes in the weight of the left and right ventricles in response to 3,3′,5-tri-iodothyronine treatment were measured; changes in expression of the c-myc, c-fos and H-ras proto-oncogenes were determined in parallel by measurement of specific messenger RNAs by Northern and dot hybridization, as well as changes in expression of β myosin heavy chain messenger RNA. 3. Treatment with 3,3′,5-tri-iodothyronine resulted in increases in both left and right ventricular weights after 3 days, an effect maintained up to 14 days. Despite an increase in left ventricular weight, levels of β myosin heavy chain, c-myc, c-fos and H-ras mRNAs in the left ventricle were unchanged; in contrast, an increase in right ventricular weight was associated with increased expression of β myosin heavy chain, c-myc and c-fos messenger RNAs. 4. These specific ventricular changes in gene expression, in the face of a hypertrophic response of both ventricles to 3,3′,5-tri-iodothyronine, suggest that the cardiac growth response to thyroid hormones reflects the well-documented secondary haemodynamic influences rather than direct gene regulatory actions of 3,3′,5-tri-iodothyronine at the transcriptional level on the genes studied. Changes in right ventricular proto-oncogene and β myosin heavy chain expression may in turn reflect an increase in right ventricular pressure load.

scholarly journals Usefulness of Speckle Tracking Echocardiography and Biomarkers for Detecting Acute Cellular Rejection After Heart Transplantation

2020 ◽  
Author(s):  
Cecília Beatriz Bittencourt Viana Cruz ◽  
Ludhmila A. Hajjar ◽  
Fernando Bacal ◽  
Marco S. Lofrano-Alves ◽  
Márcio S.M. Lima ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Right Ventricular ◽  
Speckle Tracking ◽  
Troponin I ◽  
Speckle Tracking Echocardiography ◽  
Left Ventricular ◽  
Acute Cellular Rejection ◽  
Control Group ◽  
Transplant Patients ◽  
Cellular Rejection

Abstract Background: Acute cellular rejection (ACR) is a major complication after heart transplantation. Endomyocardial biopsy (EMB) remains the gold standard for its diagnosis, but it has concerning complications. We evaluated the usefulness of speckle tracking echocardiography (STE) and biomarkers for detecting ACR after heart transplantation.Methods: We prospectively studied 60 transplant patients with normal left and right ventricular systolic function who underwent EMB for surveillance six months after transplantation. Sixty age- and sex-matched healthy individuals constituted the control group. Conventional echocardiographic parameters, left ventricular global longitudinal, radial and circumferential strain (LV-GLS, LV-GRS and LV-GCS, respectively), left ventricular systolic twist (LV-twist) and right ventricular free wall longitudinal strain (RV-FWLS) were analyzed just before the procedure. We also measured biomarkers at the same moment. Results: Among the included 60 patients, 17 (28%) had severe ACR (grade ≥ 2R), and 43 (72%) had no significant ACR (grade 0 – 1R). The absolute values of LV-GLS, LV-twist and RV-FWLS were lower in transplant patients with ACR degree ≥ 2 R than in those without ACR (12.5% ± 2.9% vs 14.8% ± 2.3%, p=0.002; 13.9° ± 4.8° vs 17.1° ± 3.2°, p=0.048; 21.4%± 3.2% vs 16.6% ± 2.9%, p<0.001; respectively), while no differences were observed between the LV-GRS or LV-GCS. All of these parameters were lower in the transplant group without ACR than in the nontransplant control group, except for the LV-twist. Cardiac troponin I levels were significantly higher in patients with significant ACR than in patients without significant ACR [0.19 ng/mL (0.09–1.31) vs. 0.05 ng/mL (0.01–0.18), p=0.007]. The combination of troponin with LV-GLS, RV FWLS and LV-Twist had an AUC (area under curve) for the detection of ACR of 0.80 (0.68 – 0.92), 0.89 (0.81 – 0.93) and 0.79 (0.66 – 0.92), respectively. Conclusion: Heart transplant patients have altered left ventricular dynamics compared with control individuals. The combination of troponin with strain parameters had higher accuracy for the detection of ACR than the isolated variables and this association might select patients with a higher risk for ACR who will benefit from an EMB procedure in the first year after heart transplantation.

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