S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

2011 ◽  
Vol 441 (1) ◽  
pp. 199-207 ◽  
Author(s):  
Ruomin Di ◽  
Xiangqi Wu ◽  
Zai Chang ◽  
Xia Zhao ◽  
Qiuting Feng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
S6 Kinase ◽  
Beneficial Effects ◽  
Therapeutic Value ◽  
Specific Deletion

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

2004 ◽  
Vol 286 (1) ◽  
pp. H381-H387 ◽  
Author(s):  
Ling Chen ◽  
Chang Xun Chen ◽  
Xiaohong Tracey Gan ◽  
Norbert Beier ◽  
Wolfgang Scholz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Infarct Size ◽  
Treatment Delay ◽  
Left Ventricular ◽  
Heart Weight ◽  
Coronary Artery Ligation ◽  
Treatment Protocols ◽  
Beneficial Effects ◽  
All Treatment

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse the maladaptive remodeling that results in heart failure. We sought to determine the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on heart failure produced by myocardial infarction in the rat and to assess whether up to 4 wk of treatment delay results in beneficial effects. Male Sprague-Dawley rats were subjected to coronary artery ligation (or a sham procedure) and followed for up to 3 mo, at which time hypertrophy and hemodynamics were determined. EMD was provided in the diet, and treatment commenced immediately or 2–4 wk after ligation. EMD significantly reduced hemodynamic abnormalities, including the elevation in left ventricular end-diastolic pressure, and diminished the loss of systolic function with all treatment protocols. Left ventricular dilatation and hypertrophy, as assessed by heart weight, cell size, and atrial natriuretic peptide (ANP) expression, were similarly reversed to sham or near-sham levels. In addition, the increased plasma ANP and pro-ANP values were reversed to levels not significantly different from sham. Surprisingly, virtually all beneficial effects were identical with all treatment protocols. These effects were observed in the absence of infarct size reduction or blood pressure-lowering effects. Our results suggest that NHE-1 inhibition attenuates and reverses postinfarction remodeling and heart failure with a treatment delay of up to 4 wk after infarction. The effect is independent of infarct size or afterload reduction, indicating a direct effect on the myocardium.

Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Abhijit Takawale ◽  
Ratnadeep Basu ◽  
Xiuhua Wang ◽  
Zamaneh Kassiri
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Response ◽  
Imaging System ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Adverse Remodeling

Introduction: The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction. Hypothesis: Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI. Results: Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p<0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium. Conclusions: This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.

scholarly journals Beneficial effects of selective HDL-raising gene transfer on survival, cardiac remodelling and cardiac function after myocardial infarction in mice

Gene Therapy ◽  
2013 ◽  
Vol 20 (11) ◽  
pp. 1053-1061 ◽  
Author(s):  
S C Gordts ◽  
I Muthuramu ◽  
E Nefyodova ◽  
F Jacobs ◽  
E Van Craeyveld ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Cardiac Remodelling ◽  
Beneficial Effects

Abstract MP202: The Effects Of Maternal Hypothyroidism On Fetal And Adult Cardiac Function

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Yijia Li ◽  
Guihong Chen ◽  
Xiaoying Zhang ◽  
Ran Zhao ◽  
Steven R Houser ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Abdominal Circumference ◽  
Left Ventricular Ejection ◽  
Heart Weight ◽  
Systematic Research ◽  
Ventricular Ejection Fraction ◽  
The Impact

Objectives: Maternal hypothyroidism (MH), a common clinical condition with a reported prevalence from 2.5% to 13%. MH could have an adverse effect on fetal cardiac development and adult heart function. However, there is a lack of systematic research for its effect on fetal and offspring’s development and cardiac function. This study aimed to determine the impact of MH on fetal and offspring’s organ structural and functional development at different gestation stages and during postnatal and puberty. Methods: MH model had been built through thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. Pups from mice that underwent TX and Sham surgery were named THD (Deficient) and THN (Normal). Times of parturition and miscarriage from TX and Sham groups were recorded. Ultrasound was performed for fetuses and/or offspring to check the gestation, miscarriage, embryo arrest, development, malformation, and cardiac function. At different postnatal days, mice were euthanized for organ development evaluation. Result: TX mice had reduced parturition frequencies and smaller litter size but increased miscarriage frequency and malformed fetuses than the sham group. In addition, THD fetuses had smaller biparietal diameter (BPD) and abdominal circumference (AC) and significantly lower left ventricular ejection fraction (LVEF) on E14.5, but not at E18.5. Tei index, a parameter representing both systolic and diastolic cardiac function, was lower in THD fetuses than in THN fetuses at both E14.5 and E18.5. The cardiac systolic and diastolic function of female TX mice after a 9-month breeding period was also abnormal. The Postnatal T4 level was not significantly different between the two groups. On and after d21 after birth, THD mice had a higher heart weight/body weight ratio and lower LVEF still d21. Conclusion: MH impaired the development and cardiac function of the fetus and young adult. In addition, MH impaired the mother's fertility and depressed cardiac function.

Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin

2019 ◽  
Vol 116 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Hairuo Lin ◽  
Yang Li ◽  
Hailin Zhu ◽  
Qiancheng Wang ◽  
Zhenhuan Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
Body Weight Ratio

Abstract Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

Cardiac function in hearts isolated from a rat model deficient in mast cells

2005 ◽  
Vol 288 (2) ◽  
pp. H632-H637 ◽  
Author(s):  
Richard H. Kennedy ◽  
Martin Hauer-Jensen ◽  
Jacob Joseph
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cardiac Function ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Balloon Catheter ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Adult Rats

Several studies have examined the role of mast cells in the myocardial response to injury such as that caused by hypertension and ischemia-reperfusion. However, little is known about the influence of mast cells on normal myocardial structure and function. The present experiments examined cardiac function in Langendorff-perfused hearts isolated from 6- and 9-mo-old male mast cell-deficient ( Ws/ Ws) and mast cell-competent rats. A fluid-filled balloon catheter was used to measure left ventricular diastolic and systolic function at increasing preload volumes. At 6 mo of age, mast cell-deficient rats showed a slight cardiac hypertrophy (as monitored by heart weight and heart weight-to-body weight ratio) but no significant change in maximum observed systolic or diastolic function. In contrast, at 9 mo of age, the mast cell-deficient group showed no signs of hypertrophy but displayed a diastolic dysfunction characterized by decreased compliance without a significant decline in maximum observed basal −dP/d tmax. There were no significant differences in maximum observed values for measures of systolic function (developed pressure and +dP/d tmax). In summary, the results of this study in adult rats suggest that mast cells influence cardiac function in the absence of injury and that observed differences between mast cell-competent and -deficient animals vary with age. Thus it is important to consider these “physiological” actions and resulting changes in function when studying effects of insult in mast cell-deficient models.

scholarly journals OSM Enhances Angiogenesis and Improves Cardiac Function after Myocardial Infarction

2015 ◽  
Vol 2015 ◽  
pp. 1-10
Author(s):  
Xiaotian Zhang ◽  
Di Zhu ◽  
Liping Wei ◽  
Zhijing Zhao ◽  
Xin Qi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Body Weight ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Oncostatin M ◽  
Border Zone ◽  
Heart Weight ◽  
Vehicle Group ◽  
Infarct Border Zone ◽  
Infarct Border

Oncostatin M (OSM) has been reported to stimulate angiogenesis by upregulating VEGF and bFGF, implying that it could be a therapeutic strategy in treating ischemic diseases. The present study was aimed at investigating whether OSM could improve cardiac function via prompting angiogenesis following myocardial infarction (MI). Wild type (WT) and Oβknock-out (Oβ−/−) mice were, respectively, randomized into sham group, MI + vehicle group, and MI + OSM group. WT mice displayed significantly impaired cardiac function after MI. OSM treatment attenuated cardiac dysfunction in WT MI mice, while Oβdeletion abrogated the protective effects. Besides, OSM attenuated heart hypertrophy and pulmonary congestion evidenced by decreased heart weight/body weight and lung weight/body weight ratio. Further, reduction of apoptosis and fibrosis in infarct border zone was observed in OSM treated WT MI mice compared with vehicle. Moreover, in WT mice subjected to MI, OSM treatment significantly increased capillary density along with upregulation of p-Akt and angiogenic factors VEGF and bFGF in comparison with vehicle, and this phenomenon was not found in Oβ−/−mice. In conclusion, OSM treatment preserved cardiac function, inhibited apoptosis and fibrosis, and stimulated angiogenesis via upregulating VEGF and bFGF in infarct border zone of ischemic myocardium, indicating that OSM could be a novel therapeutic target for MI.

Abstract 3471: Ablation Of Phospholamban And Sarcolipin Has A Deleterious Effect On SERCA Pump Activity And Cardiac Contractility

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mayilvahanan Shanmugam ◽  
Shumin Gao ◽  
Evangelia Kranias ◽  
Muthu Periasamy ◽  
Gopal J Babu
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Deleterious Effect ◽  
Contractile Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Double Knockout ◽  
Pump Activity ◽  
Serca Pump

Recent studies have been directed towards the potential therapeutic value of improving the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) function in the failing myocardium. Overexpression of SERCA pump or inhibiting the function of phospholamban (PLB) has been shown to improve the cardiac function in failing myocardium. Towards this goal, we enhanced the SERCA pump activity in both atria and ventricle by ablating its key regulators, PLB and sarcolipin (SLN). The homozygous double knockout (dKO) pups were delivered in Mendelian ratio and reached adulthood without any visible abnormalities. However, these mice develop cardiac hypertrophy. The heart weight to body weight ratio significantly increased in 3– 4 months old dKO mice (WT-3.08±0.11 vs. dKO-4.14±0.14) and is associated with enlargement of myocytes (WT-117±8 μm2 vs. dKO-166±10 μm2). Ablation of PLB and SLN did not affect the expression of major Ca2+ handling proteins including SERCA2a, calsequestrin, L-type Ca2+ channel and ryanodine receptor in both atria and ventricles. Echocardiographic measurements showed increased diastolic (WT-0.90±0.02 mm vs. dKO-1.26±0.07 mm) and systolic (WT-1.33±0.03 mm vs. dKO-1.68±0.08 mm) septal wall thicknesses and diastolic (WT-0.91±0.02 mm vs. dKO-1.15±0.07 mm) and systolic (WT-1.15±0.03 mm vs. dKO-1.35±0.07 mm) post wall thickness in 3– 4 months old dKO mice hearts. However, left ventricular end-diastolic dimension (LVEDD), LV end-systolic dimension and ejection fraction (EF, %: WT-0.73±0.12 vs. dKO-0.69±0.03) are not very different from wildtype indicating preserved contractile function in the dKO mice. Our studies therefore suggest that the enhanced Ca2+ sensitivity of cardiac SERCA pump can progressively lead to cardiac hypertrophy and may have a deleterious effect on cardiac function during pathological conditions.

Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice

2015 ◽  
Vol 309 (2) ◽  
pp. H345-H359 ◽  
Author(s):  
Sarah-Lena Puhl ◽  
Andreas Müller ◽  
Michael Wagner ◽  
Yvan Devaux ◽  
Michael Böhm ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systolic Function ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lv Function ◽  
Sham Operation ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
Underlying Mechanisms ◽  
And Function

Although exercise mediates beneficial effects in patients after myocardial infarction (MI), the underlying mechanisms as well as the question of whether an early start of exercise after MI is safe or even beneficial are incompletely resolved. The present study analyzed the effects of exercise before and reinitiated early after MI on cardiac remodeling and function. Male C57BL/6N mice were housed sedentary or with the opportunity to voluntarily exercise for 6 wk before MI induction (ligation of the left anterior descending coronary artery) or sham operation. After a 5-day exercise-free phase after MI, mice were allowed to reexercise for another 4 wk. Exercise before MI induced adaptive hypertrophy with moderate increases in heart weight, cardiomyocyte diameter, and left ventricular (LV) end-diastolic volume, but without fibrosis. In sedentary mice, MI induced eccentric LV hypertrophy with massive fibrosis but maintained systolic LV function. While in exercised mice gross LV end-diastolic volumes and systolic function did not differ from sedentary mice after MI, LV collagen content and thinning of the infarcted area were reduced. This was associated with ameliorated activation of inflammation, mediated by TNF-α, IL-1β, and IL-6, as well as reduced activation of matrix metalloproteinase 9. In contrast, no differences in the activation patterns of various MAPKs or adenosine receptor expressions were observed 5 wk after MI in sedentary or exercised mice. In conclusion, continuous exercise training before and with an early reonset after MI ameliorates adverse LV remodeling by attenuating inflammation, fibrosis, and scar thinning. Therefore, an early reonset of exercise after MI can be encouraged.

scholarly journals Sex-related changes in cardiac function following myocardial infarction in mice

2008 ◽  
Vol 295 (2) ◽  
pp. R528-R534 ◽  
Author(s):  
Krystyna M. Shioura ◽  
David L. Geenen ◽  
Paul H. Goldspink
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Weight Ratio ◽  
Compensatory Hypertrophy ◽  
Heart Weight ◽  
Stroke Work ◽  
Male Mice ◽  
Significant Deterioration

Recent awareness of cardiovascular diseases as a number one killer of the middle-aged women has prompted interest in sex differences leading to heart failure (HF). Therefore, we evaluated cardiac function in female and male mice following myocardial infarction (MI) using the Millar pressure-volume (P-V) conductance system in vivo, at time points corresponding to early (2 wk), late compensatory hypertrophy (4 wk), and decompensation (10 wk) to HF. A significant deterioration of the load dependent and independent hemodynamic measurements occurred in both female and male mice during the early phase of hypertrophy. Later, compensatory hypertrophy was marked by a normalization of volumes to control levels in females compared with males. The most notable differences between sexes occurred in the measurements of cardiac contractility during the decompensation to HF. In females, there was a significant improvement in contractility compared with males, which was apparent in the load-independent measurements of preload recruitable stroke work (10 wk post-MI, female = 48.7 ± 8.0 vs. male = 25.2 ± 1.8 mmHg, P < 0.05) and maximum dP/d t vs. maximum end-diastolic volume (10 wk post-MI, female=359 ± 58 vs. male=149 ± 28 mmHg·s−1·μl−1, P < 0.05). Despite these differences, there were no differences in the heart weight to body weight ratio and infarct size between the sexes. These data demonstrate that compensatory hypertrophy is associated with an improvement in contractility and a delayed decompensation to HF in females. However, compensatory hypertrophy in males appears to be undermined by a steady decline in contractility associated with decompensation to HF.

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