Diastolic Dysfunction During Ischemia: Role of Glycolytic ATP Generation

1994 ◽  
pp. 125-134
Author(s):  
Carl S. Apstein
2020 ◽  
Vol 21 (24) ◽  
pp. 9744
Author(s):  
Heng Zeng ◽  
Xiaochen He ◽  
Jian-Xiong Chen

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. Methods and Results: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E’ velocity/A’ velocity (E’/A’) ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. Conclusions: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.


2013 ◽  
Vol 62 (18) ◽  
pp. C89-C90
Author(s):  
Erdem Özel ◽  
Ahmet Taştan ◽  
Samet Uyar ◽  
Ali Öztürk ◽  
Talat Tavlı

2018 ◽  
Vol 315 (5) ◽  
pp. H1477-H1485 ◽  
Author(s):  
Kimiko Yamamoto ◽  
Hiromi Imamura ◽  
Joji Ando

Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca2+ signaling plays a critical role in this mechanotransduction, i.e., ECs release ATP in the caveolae in response to shear stress and, in turn, the released ATP activates P2 purinoceptors, which results in an influx into the cells of extracellular Ca2+. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here, we demonstrated that cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device, and changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon exposure of the cells to flow, mitochondrial ATP levels increased, which was both reversible and dependent on the intensity of shear stress. Inhibitors of the mitochondrial electron transport chain and ATP synthase as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear stress-induced mitochondrial ATP generation, resulting in the loss of ATP release and influx of Ca2+ into the cells. These results suggest the novel role of mitochondria in transducing shear stress into ATP generation: ATP generation leads to ATP release in the caveolae, triggering purinergic Ca2+ signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms. NEW & NOTEWORTHY The mechanism of how vascular endothelial cells sense shear stress generated by blood flow and transduce it into functional responses remains unclear. Real-time imaging of mitochondrial ATP demonstrated the novel role of endothelial mitochondria as mechanosignaling organelles that are able to transduce shear stress into ATP generation, triggering ATP release and purinoceptor-mediated Ca2+ signaling within the cells.


2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Keyvan Yousefi ◽  
Wen Ding ◽  
Lina A Shehadeh

HFpEF is an increasingly prevalent syndrome associated with impaired myocardial energetics, for which no etiologic therapy is available. Osteopontin (OPN) is a matricellular protein that is upregulated in the circulation of HFpEF patients, and reported to induce mitochondrial stress in rodent cardiomyocytes. Here we evaluate the role of circulating OPN in regulating myocardial function in the nephrotic Col4a3 -/- mouse model of HFpEF. We performed extensive cardiac, biochemical and mitochondrial analyses of the Col4a3 -/- mouse and found a striking HFpEF phenotype. We showed OPN levels were elevated in Col4a3 -/- mice (FC=2.1, n=6; p<.01). Col4a3 -/- mice were hypertensive, had diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis - all of which were ameliorated in Col4a3 -/- OPN -/- mice (n=5-20; p<.05). Col4a3 -/- hearts had dysmorphic mitochondria (EM), lowered antioxidant capacity as a 50% reduction in GSH/GSSG ratio (n=6; p<.05) and lower protein levels of mitochondrial respiratory complexes I, II and IV (p<.05). Flux assay in adult cardiomyocytes showed that maximal respiration was reduced in Col4a3 -/- hearts (575.84±37.6 vs 322.34±25.48 pmol/min in WT, n=9; p<.0001). Microarray data (validated by mitochondrial blot) implicated OGDHL as decreased in Col4a3 -/- hearts but increased in double knockout Col4a3 -/- OPN -/- hearts compared to WT (n=3; p<.05). OGDH activity was also lower in Col4a3 -/- hearts (17.1±7.3 vs 2.5±1.1 mU/mg in WT; n=6; p<.05). In Col4a3 -/- mice, heart-specific AAV9-mediated overexpression of OGDHL, similar to global OPN KO, improved survival by ~50-100% (p<.0001). Isovolumetric relaxation time, a marker of diastolic dysfunction, which is prolonged in Col4a3 -/- mice (26.17 vs 15.30±1 ms, n=26; p<.001) was decreased in Col4a3 -/- OPN -/- mice (18.1±1 ms, n=37; p<.01) as well as in AAV9-cTnT-OGDHL-treated Col4a3 -/- mice (16.7±2.5 ms, n=8; p<.05). In conclusion, we present a new mouse model for HFpEF in which diastolic function and lifespan can be improved by genetic deletion of OPN or cardiac OGDHL gene therapy. Our results elucidate for the first time the pivotal roles of circulating OPN and cardiac OGDHL in HFpEF pathophysiology and present two related potential therapeutic targets for HFpEF.


2019 ◽  
Vol 35 (7) ◽  
pp. 1231-1240 ◽  
Author(s):  
Iacopo Fabiani ◽  
◽  
Nicola Riccardo Pugliese ◽  
Salvatore La Carrubba ◽  
Lorenzo Conte ◽  
...  

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
R C Rimbas ◽  
L M Luchian ◽  
A M Chitroceanu ◽  
M Rimbas ◽  
S I Visoiu ◽  
...  

Abstract Funding Acknowledgements “This work was supported by a grant of Ministery of Research and Innovation, CNCS-UEFISCDI, project number PN-III-P1-1-TE-2016-0669, within PNCDI III” Background Cirrhotic cardiomyopathy (CCM) is defined as a cardiac dysfunction that includes mainly diastolic dysfunction (DD), generated by liver cirrhosis (LC). Its present diagnosis is based mostly on 2D conventional transthoracic echocardiography (TTE), with focus on diastolic dysfunction. However, there is no standardized algorithm for diagnosis of CCM. Role of the new methods, such as speckle tracking echocardiography (STE), for the diagnosis of CCM is still controversial. Aim. To assess left atrial (LA) function by STE in LC, on top of conventional TTE, in order to establish role of LA function for the diagnosis of CCM. Methods 107 subjects were assessed by TTE and STE: 52 patients with LC (57 ± 9 yrs, 23 males), free of any cardiovascular disease or diabetes, and 55 age-matched normal subjects. TTE was used to measure LV indexed volumes and ejection fraction (LVEF), E/E’ ratio, left atrial volume index (LAVi), and systolic pulmonary arterial pressure (sPAP); STE to measure global longitudinal strain (GLS) and LA functions: reservoir function by strain from MVC to MVO (LASr) and positive strain rate (LASRr), conduit function by strain from MVO to onset of atrial contraction (LAScd) and early negative strain rate during conduit phase (LASRcd), LA pump function by negative strain at MVC (LASct) and late negative strain rate during atrial contraction phase (LASRct) (Figure). NTproBNP was measured in all patients. Results LC patients vs. controls had lower SBP (112 ± 15 vs. 122 ± 12, P &lt; 0.001), higher LV volumes and NTproBNP, but similar LVEF. They had lower GLS, and higher E/E’, LAVi, and sPAP, suggesting higher LV filling pressure (Table). Meanwhile, they had lower LA reservoir, conduit, and pump functions(Table). By using current algorithm for the diagnosis of DD, 21% of LC patients had DD, 48% had no DD, and 31% had indeterminate grade. By adding assessment of LA reservoir function by STE (LASr &lt; 35%) to the DD algorithm, 50% of patients had DD, without any indeterminate cases. Conclusion LC patients have longitudinal systolic LV dysfunction, diastolic dysfunction with higher estimated LV filling pressure, and lower LA reservoir, conduit, and pump functions. By adding LA deformation analysis by STE to the current diagnosis algorithm, better characterization of CCM is possible. Table Group (N) NTproBNP ng/ml GLS (%) E/E’ LAVi (ml/m2) sPAP (mmHg) LASr (%) LASRr LAScd (%) LASRcd LASRct LC (52) 215 ± 258 -20.8 ± 3 8.5 ± 2.3 44 ± 14 27 ± 9 28 ± 9 1.29 ± 0.4 14.7 ± 8.1 -1.2 ± 0.42 -1.64 ± 0.47 Controls (55) 44 ± 43 -22 ± 2 7.6 ±2.3 28 ±6.5 21 ± 8 35 ± 4 1.54 ± 0.4 18.3 ± 6.7 -1.7 ± 0.61 -1.93 ± 0.44 P value &lt;0.001 0.05 0.05 0.001 0.003 0.011 0.002 0.014 0.001 0.002 Abstract P324 Figure


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