STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium

2006 ◽  
Vol 291 (2) ◽  
pp. H797-H803 ◽  
Author(s):  
Karyn L. Butler ◽  
Lynn C. Huffman ◽  
Sheryl E. Koch ◽  
Harvey S. Hahn ◽  
Judith K. Gwathmey
Keyword(s):  
Ischemic Preconditioning ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Posterior Wall Thickness ◽  
Hypertrophied Myocardium ◽  
Developed Pressure

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 ± 58 vs. 1,028 ± 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/d tmax; 4,648 ± 309 vs. 2,737 ± 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum −dP/d t (−dP/d tmin; −2,239 ± 205 vs. −1,215 ± 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/d tmax(4,648 ± 309 vs. 3,241 ± 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and −dP/d tmin(−2,239 ± 205 vs. −1,323 ± 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.

Captopril prevents vascular and fibrotic changes but not cardiac hypertrophy in aortic-banded rats

1996 ◽  
Vol 271 (3) ◽  
pp. H906-H913 ◽  
Author(s):  
C. P. Regan ◽  
P. G. Anderson ◽  
S. P. Bishop ◽  
K. H. Berecek
Keyword(s):  
Cardiac Hypertrophy ◽  
Coronary Vessels ◽  
Pressure Overload ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Vessel Morphology ◽  
Sprague Dawley Rats ◽  
Quantitative Image

To determine the role of the renin-angiotensin system (RAS) on cardiovascular remodeling in a pressure overload model of cardiac hypertrophy, a subdiaphragmatic aortic band was placed in adult male, Sprague-Dawley rats. Rats were left untreated (AB) or given captopril (Cap, 400 mg/l) (AB-Cap). Sham-operated controls were either left untreated (S) or given Cap (S-Cap). After 4 wk, rats were catheterized, and carotid and femoral mean arterial pressures (CMAP and FMAP in mmHg, respectively) were recorded. Hearts were isolated, and minimal coronary resistance (MCR) was determined. Hearts were then perfusion fixed, total and regional heart weights were recorded, and sections were processed for vessel morphology. Changes in coronary artery medical thickness and perivascular fibrosis were assessed by quantitative image analysis. CMAP was significantly higher in AB and AB-Cap than S or S-Cap rats (P < 0.05). There was no difference in FMAP in AB vs. S rats, but AB-Cap and S-Cap had lower FMAP values than S rats. Total heart weight and left ventricular weight-to-body weight ratios were increased in AB and AB-Cap rats compared with S and S-Cap rats (P < 0.05). MCR of AB was greater than S and S-Cap rats. MCR of AB-Cap rats was significantly greater than S and S-Cap rats but was significantly less than AB rats. In coronary vessels, medial thickness was greatest in AB, whereas there was no difference among AB-Cap, S, and S-Cap rats. Similarly, the increase in perivascular fibrosis was greatest in AB rats, and there was no difference among AB-Cap, S, and S-Cap rats. These data suggest that the RAS, independent of increased arterial pressure, is critical for the development of the vascular and fibrotic changes that occur in this model of pressure overload hypertrophy.

scholarly journals Rats are protected from the stress of chronic pressure overload compared with mice

2020 ◽  
Vol 318 (5) ◽  
pp. R894-R900 ◽  
Author(s):  
Koichi Nishimura ◽  
Marko Oydanich ◽  
Jie Zhang ◽  
Denis Babici ◽  
Diego Fraidenraich ◽  
...  
Keyword(s):  
Troponin I ◽  
Diastolic Pressure ◽  
Pressure Overload ◽  
Wall Stress ◽  
Left Ventricular ◽  
Pressure Gradients ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Systolic And Diastolic Function ◽  
Systolic Wall Stress

The goal of this investigation was to compare the effects of chronic (4 wk) transverse aortic constriction (TAC) in Sprague-Dawley rats and C57BL/6J mice. TAC, after 1 day, induced similar left ventricular (LV) pressure gradients in both rats ( n = 7) and mice ( n = 7) (113 ± 5.4 vs. 103 ± 11.5 mmHg), and after 4 wk, the percent increase in LV hypertrophy, as reflected by LV/tibial length (51% vs 49%), was similar in rats ( n = 12) and mice ( n = 12). After 4 wk of TAC, LV systolic and diastolic function were preserved in TAC rats. In contrast, in TAC mice, LV ejection fraction decreased by 31% compared with sham, along with increases in LV end-diastolic pressure (153%) and LV systolic wall stress (86%). Angiogenesis, as reflected by Ki67 staining of capillaries, increased more in rats ( n = 6) than in mice ( n = 6; 10 ± 2 vs. 6 ± 1 Ki67-positive cells/field). Myocardial blood flow fell by 55% and coronary reserve by 28% in mice with TAC ( n = 4), but they were preserved in rats ( n = 4). Myogenesis, as reflected by c-kit-positive myocytes staining positively for troponin I, is another mechanism that can confer protection after TAC. However, the c-kit-positive cells in rats with TAC were all negative for troponin I, indicating the absence of myogenesis. Thus, rats showed relative tolerance to severe pressure overload compared with mice, with mechanisms involving angiogenesis but not myogenesis.

Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats

2001 ◽  
Vol 91 (4) ◽  
pp. 1545-1554 ◽  
Author(s):  
Korinne N. Jew ◽  
Russell L. Moore
Keyword(s):  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Diastolic Stiffness ◽  
Pressure Development ◽  
Increased Sensitivity ◽  
Developed Pressure

In this study, we sought to determine whether there was any evidence for the idea that cardiac ATP-sensitive K+ (KATP) channels play a role in the training-induced increase in the resistance of the heart to ischemia-reperfusion (I/R) injury. To do so, the effects of training and an KATP channel blocker, glibenclamide (Glib), on the recovery of left ventricular (LV) contractile function after 45 min of ischemia and 45 min of reperfusion were examined. Female Sprague-Dawley rats were sedentary (Sed; n = 18) or were trained (Tr; n = 17) for >20 wk by treadmill running, and the hearts from these animals used in a Langendorff-perfused isovolumic LV preparation to assess contractile function. A significant increase in the amount of 72-kDa class of heat shock protein was observed in hearts isolated from Tr rats. The I/R protocol elicited significant and substantial decrements in LV developed pressure (LVDP), minimum pressure (MP), rate of pressure development, and rate of pressure decline and elevations in myocardial Ca2+ content in both Sed and Tr hearts. In addition, I/R elicited a significant increase in LV diastolic stiffness in Sed, but not Tr, hearts. When administered in the perfusate, Glib (1 μM) elicited a normalization of all indexes of LV contractile function and reductions in myocardial Ca2+content in both Sed and Tr hearts. Training increased the functional sensitivity of the heart to Glib because LVDP and MP values normalized more quickly with Glib treatment in the Tr than the Sed group. The increased sensitivity of Tr hearts to Glib is a novel finding that may implicate a role for cardiac KATP channels in the training-induced protection of the heart from I/R injury.

Abstract 30: 4-PBA Prevents TAC-induced Myocardial Hypertrophy and Interstitial Fibrosis by Attenuating ER Stress in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Tao Luo ◽  
Baihe Chen ◽  
Xianbao Wang
Keyword(s):  
Er Stress ◽  
Therapeutic Effect ◽  
Wall Thickness ◽  
Myocardial Hypertrophy ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Posterior Wall Thickness ◽  
Imaging Observation

Background: Recently, 4-phenylbutyric acid (4-PBA) has been recognized as a potent ER stress inhibitor and a histone deacetylase inhibitor, but its therapeutic effect in cardiovascular diseases is still not fully understood. Our previous study indicated that attenuation of ER stress by administration of low dosage of 4-PBA (20 mg/kg/d) prevented post-infarction-induced cardiac rupture and remodeling through modulating both cardiac apoptosis and fibrosis in the mouse model of myocardial infarction. However, little is known whether the administration of 4-PBA is effective for hypertrophic heart disease. The aim of this study is therefore to test the therapeutic effect of 4-PBA on pressure-overload induced myocardial hypertrophy. Methods and Results: Transverse aortic constriction (TAC) was used to produce pressure-overload in C57BL/6 male mice for 4 weeks. After surgery, 4-PBA (20mg/kg/d) or 0.9% NaCL was intraperitoneally injected daily. At the end of 4 weeks, the survivals were underwent high-resolution echocardiographic imaging observation. The results showed that the left ventricular posterior wall thickness at end systole (LVPWs) and left ventricular posterior wall thickness at end diastole (LVPWd) were increased in TAC group. Administration of 4-PBA ameliorated this hypertrophic effect. Autopsy also confirmed the anti-hypertrophic effect of 4-PBA. Masson-staining found that there was no difference in perivascular fibrosis between TAC and TAC+4-PBA groups. However, myocardial interstitial fibrosis and collagen deposition were significant decreased by 4-PBA. We finally detected the ER stress and histone acetylation using western blotting. Our results showed that 4-PBA, at the dosage of 20 mg/kg/day, decreased the expression of CHOP and had no effect on histone 3 acetylation. Conclusion: These findings indicate that attenuating ER stress by 4-PBA maybe a promising therapeutic strategy to prevent pressure-overload induced myocardial hypertrophy and interstitial fibrosis.

scholarly journals Novel Model of Pulmonary Artery Banding Leading to Right Heart Failure in Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Masataka Hirata ◽  
Daiki Ousaka ◽  
Sadahiko Arai ◽  
Michihiro Okuyama ◽  
Suguru Tarui ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Right Heart Failure ◽  
Pulmonary Artery Banding ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sprague Dawley Rats ◽  
The Right

Background. Congenital heart diseases often involve chronic pressure overload of the right ventricle (RV) which is a major cause of RV dysfunction. Pulmonary artery (PA) banding has been used to produce animal models of RV dysfunction. We have devised a new and easier method of constricting the PA and compared it directly with the partial ligation method.Methods. Eight-week-old male Sprague-Dawley rats (240–260 g) were divided into three groups: sham operation, partial pulmonary artery ligation (PAL) procedure, and pulmonary artery half-closed clip (PAC) procedure. RV function and remodeling were determined by echocardiography and histomorphometry.Results. Surgical mortality was significantly lower in the PAC group while echocardiography revealed significantly more signs of RV dysfunction. At the 8th week after surgery RV fibrosis rate was significantly higher in the PAC group.Conclusions. This procedure of pulmonary artery banding in rats is easier and more efficient than partial ligation.

Pressure overload differentially affects respiratory capacity in interfibrillar and subsarcolemmal mitochondria

2013 ◽  
Vol 304 (4) ◽  
pp. H529-H537 ◽  
Author(s):  
Michael Schwarzer ◽  
Andrea Schrepper ◽  
Paulo A. Amorim ◽  
Moritz Osterholt ◽  
Torsten Doenst
Keyword(s):  
Electron Microscopy ◽  
Cell Function ◽  
Citrate Synthase ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Respiratory Capacity ◽  
Subsarcolemmal Mitochondria

Years ago a debate arose as to whether two functionally different mitochondrial subpopulations, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), exist in heart muscle. Nowadays potential differences are often ignored. Presumably, SSM are providing ATP for basic cell function, whereas IFM provide energy for the contractile apparatus. We speculated that two distinguishable subpopulations exist that are differentially affected by pressure overload. Male Sprague-Dawley rats were subjected to transverse aortic constriction for 20 wk or sham operation. Contractile function was assessed by echocardiography. Heart tissue was analyzed by electron microscopy. Mitochondria were isolated by differential centrifugation, and respiratory capacity was analyzed using a Clark electrode. Pressure overload induced left ventricular hypertrophy with increased posterior wall diameter and impaired contractile function. Mitochondrial state 3 respiration in control was 50% higher in IFM than in SSM. Pressure overload significantly impaired respiratory rates in both IFM and SSM, but in SSM to a lower extent. As a result, there were no differences between SSM and IFM after 20 wk of pressure overload. Pressure overload reduced total citrate synthase activity, suggesting reduced total mitochondrial content. Electron microscopy revealed normal morphology of mitochondria but reduced total mitochondrial volume density. In conclusion, IFM show greater respiratory capacity in the healthy rat heart and a greater depression of respiratory capacity by pressure overload than SSM. The differences in respiratory capacity of cardiac IFM and SSM in healthy hearts are eliminated with pressure overload-induced heart failure. The strong effect of pressure overload on IFM together with the simultaneous appearance of mitochondrial and contractile dysfunction may support the notion of IFM primarily producing ATP for contractile function.

Right ventricular TNF resistance during endotoxemia: the differential effects on ventricular function

2007 ◽  
Vol 293 (5) ◽  
pp. R1893-R1897 ◽  
Author(s):  
Troy A. Markel ◽  
Paul R. Crisostomo ◽  
Meijing Wang ◽  
Jeremy L. Herrmann ◽  
Aaron M. Abarbanell ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Ventricular Function ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Endotoxin Exposure ◽  
Sprague Dawley Rats ◽  
Developed Pressure ◽  
The Right ◽  
Rv Function

Right and left ventricular myocytes originate from different cellular progenitors; however, it is unknown whether these cells differ in their response to endotoxemia. We hypothesized that 1) the percentage of endotoxemic functional depression within the right ventricle (RV) would be smaller than that of the left ventricle; and 2) that better RV function would correlate with lower levels of right ventricular TNF production. Adult Sprague-Dawley rats were divided into right and left control and endotoxin groups. Controls received vehicle, while endotoxin groups received LPS at 20 mg/kg ip. Hearts were excised either 2 or 6 h after injection. Hearts excised at 2 h were assayed for TNF, IL-6, TNF receptor 1 (TNFR1), TNFR2, and via ELISA, while hearts excised at 6 h were assayed via the Langendorff model. The percentage of cardiac functional depression, exhibited as developed pressure, contractility, and rate of relaxation (expressed as a percentage of control) was significantly smaller in right ventricles compared with left ventricles following endotoxin exposure. Tissue levels of TNF were significantly elevated in both right and left ventricles 2 h after endotoxin exposure, and right ventricular endotoxin groups expressed higher levels of TNF compared with their left ventricular counterparts. No significant differences in IL-6, TNFR1, or TNFR2 levels were noted between endotoxin-exposed ventricles. This is the first study to demonstrate that right and left ventricular function differs after endotoxin exposure.

scholarly journals Cholecystokinin Expression in the Development of Postinfarction Heart Failure

2017 ◽  
Vol 43 (6) ◽  
pp. 2479-2488 ◽  
Author(s):  
Xiaoying Dong ◽  
Can Wang ◽  
Jingqi Zhang ◽  
Siyue Wang ◽  
Hongjian Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Western Blotting ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Expression Levels ◽  
Sprague Dawley Rats ◽  
Heart Failure Progression

Background/Aims: Cholecystokinin (CCK) is expressed in cardiomyocytes and may also play an important role in cardiovascular regulation. Clinical studies have shown that plasma CCK levels are an independent marker of cardiovascular mortality in cardiac disease. However, whether the development of postinfarction heart failure is associated with changes in CCK expression is unknown. Methods: To investigate CCK expression patterns and the association between CCK expression and heart functional parameters, we randomized male Sprague-Dawley rats into myocardial infarction (MI) or sham operation (SO) groups. CCK expression levels were assessed by western blotting, immunohistochemistry, real-time polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) at different time points (2, 4 or 6 weeks) after surgery. Brain natriuretic peptide (BNP) concentrations were determined using Western blotting and ELISA, myocardial morphology was assessed by microscopy. Results: Plasma CCK and BNP levels were significantly increased in all the MI groups compared with the corresponding SO groups. However, the degree to which myocardial CCK mRNA and protein expression levels were increased the MI groups compared with the SO groups was greater in the 4- and 6-week groups than in the 2-week group. Furthermore, plasma CCK levels were positively correlated with BNP concentrations and left ventricular end-systolic diameter (LVDs) and significantly negatively correlated with the ejection fraction (EF) and shortening fraction (SF) in model animals. Conclusions: Heart failure progression after infarction is associated with upregulated CCK levels; thus, CCK may be useful as a novel marker of heart failure.

AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium

1999 ◽  
Vol 277 (6) ◽  
pp. H2482-H2487 ◽  
Author(s):  
Karyn L. Butler ◽  
Alice H. Huang ◽  
Judith K. Gwathmey
Keyword(s):  
Ischemic Preconditioning ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Rat Myocardium ◽  
Sprague Dawley ◽  
Isolated Hearts ◽  
Sd Rats ◽  
Developed Pressure

The purpose of this study was to determine whether ischemic preconditioning protects contractile function in hypertrophied rat myocardium from ischemia-reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for 2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body weight ratios were higher in salt-sensitive rats than in SD rats (6.9 ± 0.2 vs. 4.7 ± 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was administered losartan (10 mg ⋅ kg−1 ⋅ day−1), an AT1-receptor blocker, for 1 wk before the study. Isolated hearts were preconditioned with transient ischemia before global I/R. After I/R, preconditioned hypertrophied hearts exhibited greater recovery of left ventricular developed pressure compared with that of preconditioned normal hearts (73 ± 8 vs. 18 ± 8%, P < 0.01). Left ventricular developed pressure was further enhanced by losartan in both hypertrophied and normal myocardium (99 ± 5 vs. 73 ± 8%, P < 0.05 and 97 ± 15 vs. 18 ± 8%, P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced contractile dysfunction by ischemic preconditioning. Losartan improves the ischemic tolerance of normal and hypertrophied myocardium.

Elucidation of the mechanism of action of pinitol against pressure overload–induced cardiac hypertrophy and fibrosis in an animal model of aortic stenosis

2021 ◽  
Vol 85 (3) ◽  
pp. 643-655
Author(s):  
Xiaojing Hu ◽  
Yuanyuan Zhu ◽  
Xiaoyan L V ◽  
Zhanbin Feng
Keyword(s):  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Abdominal Aortic ◽  
Sprague Dawley Rats ◽  
Tnf Α

ABSTRACT The long-term imposition of pressure overload on the cardiac tissue causes left ventricular hypertrophy (LVH) and cardiac fibrosis. Pinitol has been reported to possess antioxidant potential. The aim was to evaluate the efficacy of pinitol against pressure overload–induced cardiac hypertrophy and fibrosis in the aortic stenosis (AS) rat model. Cardiac hypertrophy was produced in Sprague-Dawley rats by abdominal aortic constriction and treated with lisinopril (15 mg/kg) or pinitol (5, 10, and 20 mg/kg). Pressure overload–induced alterations in hemodynamic and left ventricular function tests, cardiac SOD, GSH, MDA, NO, Na-K-ATPase, and mitochondrial complex enzyme levels were significantly attenuated by pinitol. The upregulated mRNA expressions of cardiac ANP, BNP, cTn-I, TNF-α, IL-1β, IL-6, Bax, Caspase-3, collagen-I, and cardiac apoptosis were markedly downregulated by pinitol. In conclusion, pinitol ameliorated pressure overload–induced LVH and fibrosis via its anti-inflammatory, antioxidant, antifibrotic, and antiapoptotic potential in experimental AS.

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