scholarly journals Voluntary exercise may activate components of pro-survival risk pathway in the rat heart and potentially modify cell proliferation in the myocardium

2019 ◽  
pp. 581-588 ◽  
Author(s):  
L. Lonek ◽  
A. Puhova ◽  
L. Griecsova-Kindernay ◽  
S.P. Patel ◽  
V. Zohdi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Left Ventricular ◽  
Voluntary Exercise ◽  
Male Rats ◽  
Brdu Incorporation ◽  
Risk Pathway ◽  
Survival Risk ◽  
Modify Cell

Although physical exercise is known to reduce size of infarction, incidence of ventricular arrhythmias, and to improve heart function, molecular mechanisms of this protection are not fully elucidated. We explored the hypothesis that voluntary running, similar to adaptive interventions, such as ischemic or remote preconditioning, may activate components of pro-survival (RISK) pathway and potentially modify cell proliferation. Sprague-Dawley adult male rats freely exercised for 23 days in cages equipped with running wheels, while sedentary controls were housed in standard cages. After 23 days, left ventricular (LV) myocardial tissue samples were collected for the detection of expression and activation of RISK proteins (WB). The day before, a marker of cell proliferation 5-bromo-2'-deoxyuridine (BrdU) was given to all animals to detect its incorporation into DNA of the LV cells (ELISA). Running increased phosphorylation (activation) of Akt, as well as the levels of PKCε and phospho-ERK1/2, whereas BrdU incorporation into DNA was unchanged. In contrast, exercise promoted pro-apoptotic signaling - enhanced Bax/Bcl-2 ratio and activation of GSK-3β kinase. Results suggest that in the rat myocardium adapted to physical load, natural cardioprotective processes associated with physiological hypertrophy are stimulated, while cell proliferation is not modified. Up-regulation of pro-apoptotic markers indicates potential induction of cell death mechanisms that might lead to maladaptation in the long-term.

Profound cardioprotection with timolol in a female rat model of aging-related altered left ventricular function

2011 ◽  
Vol 89 (4) ◽  
pp. 277-288 ◽  
Author(s):  
Nazli N. Sozmen ◽  
Erkan Tuncay ◽  
Ayca Bilginoglu ◽  
Belma Turan
Keyword(s):  
Antioxidant System ◽  
Ventricular Myocytes ◽  
Heart Function ◽  
Thioredoxin Reductase ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Beneficial Effects ◽  
Age Related

Increasing evidence shows a marked beneficial effect with β-blockers in heart dysfunction via scavenging reactive oxygen species. Previously we showed that chronic treatment with either timolol or propranolol possessed similar beneficial effects for heart function in male rats as age increased, whereas only timolol exerted similar benefits in female rats. Therefore, in this study, we aimed first to examine the cellular bases for age-related alterations in excitation–contraction coupling in ventricular myocytes from female rats and, second, to investigate the hypothesis that age-related changes in [Ca2+]ihomeostasis and receptor-mediated system can be prevented with chronic timolol treatment. Chronic timolol treatment of 3-month-old female rats abolished age-related decrease in left ventricular developed pressure and the attenuated responses to β-adrenoreceptor stimulation. It also normalized the altered parameters of [Ca2+]itransients, decreased Ca2+loading of sarcoplasmic reticulum and increased basal [Ca2+]i, and decreased L-type Ca2+currents in 12-month-old female rats compared with the 3-month-old group. Adenylyl cyclase activity, β-adrenoreceptor affinity to its agonist, and β-adrenoreceptor density of the 12-month-old group are normalized to those of the 3-month-old group. Moreover, timolol treatment prevented dysfunction of the antioxidant system, including increased lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and decreased activities of thioredoxin reductase and glucose-6-phosphate dehydrogenase, in the left ventricle of hearts from the 12-month-old group. Our data confirmed that aging-related early myocardial impairment is primarily related to a dysfunctional antioxidant system and impairment of Ca2+homeostasis, which can be prevented with chronic timolol treatment.

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.

Abstract 042: Radiation-Associated Cardiovascular Risks for Future Deep-Space Missions

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Xinhua Yan ◽  
Sharath P Sasi ◽  
Hannah Gee ◽  
Juyong Lee ◽  
Yongyao Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Dose ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Heart Function ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Cardiovascular Risks ◽  
Compensatory Mechanisms ◽  
Negative Effect

During the future Moon and Mars missions astronauts will be exposed to space radiation (IR) for extended time. The effect of cosmic IR during and after space flights on cardiovascular (CV) system is unknown. Nine-month old C57BL/6N male mice were IR once with proton 50 cGy or 56Fe 15 cGy, both at 1 GeV/nucleon. We evaluated IR-induced biological responses - underlying molecular mechanisms, calcium handling, signal transduction and gene expression. Cardiac function was assessed by echocardiography and hemodynamic measurements. Left ventricular end diastolic pressure (LVEDP) was increased in 56Fe mice 1 and 3 months post-IR (p<0.001). One month post-IR, compared to control, proton- and 56Fe-IR sarcolemmal Na+-Ca2+ exchanger (NCX) (p<0.007) and sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a, p<0.02) were both increased more than 200% and p-p38 was decreased 400% (p<0.05), suggesting activation of compensatory mechanisms in [Ca2+]i handling in these hearts. By 3 months, compared to control, proton- and 56Fe-IR hearts SERCA2a and p-Creb1 was decreased 200-500% (p<0.02), suggesting reduced capacity in intracellular [Ca2+]i handling, suggesting that [Ca2+]i handling dysfunction combined with LVEDP increase in 56Fe-IR may be due to prolonged activation of compensatory mechanisms that lead to changes in SERCA2a and p-Creb1 levels. By 10 months, compared to control, LVESP was decreased in proton- and 56Fe-IR (p<0.03), suggesting IR-associated decrease in contractile function. However, compared to age-matched controls (18 months), the LVEDP was increased (p<0.05) and dP/dt Min was decreased (p<0.02) in proton-IR but not 56Fe-IR mice. This data suggests that after 10 months proton- but not 56Fe-IR affects considerably contractile and relaxation functions during aging. Our longitudinal 1, 3 and 10 months studies reveal that a single full body low dose proton- and 56Fe-IR have long-lasting negative effect on heart homeostasis during aging. The divergent effects of low dose proton vs. 56Fe-IR on heart function during aging suggest significantly different biological mechanisms responsible for this ion-dependent dichotomy over 10 months post-IR and necessitate further studies into underlying molecular mechanisms.

Age-related changes in cardiac structure and function in Fischer 344 × Brown Norway hybrid rats

2006 ◽  
Vol 290 (1) ◽  
pp. H304-H311 ◽  
Author(s):  
Timothy A. Hacker ◽  
Susan H. McKiernan ◽  
Pamela S. Douglas ◽  
Jonathan Wanagat ◽  
Judd M. Aiken
Keyword(s):  
Heart Function ◽  
Weight Ratio ◽  
Volume Density ◽  
Left Ventricular ◽  
Male Rats ◽  
Brown Norway ◽  
Cardiac Structure ◽  
F1 Hybrid ◽  
Fischer 344 ◽  
Lv Mass

The effects of aging on cardiovascular function and cardiac structure were determined in a rat model recommended for gerontological studies. A cross-sectional analysis assessed cardiac changes in male Fischer 344 × Brown Norway F1 hybrid rats (FBN) from adulthood to the very aged ( n = 6 per 12-, 18-, 21-, 24-, 27-, 30-, 33-, 36-, and 39-mo-old group). Rats underwent echocardiographic and hemodynamic analyses to determine standard values for left ventricular (LV) mass, LV wall thickness, LV chamber diameter, heart rate, LV fractional shortening, mitral inflow velocity, LV relaxation time, and aortic/LV pressures. Histological analyses were used to assess LV fibrotic infiltration and cardiomyocyte volume density over time. Aged rats had an increased LV mass-to-body weight ratio and deteriorated systolic function. LV systolic pressure declined with age. Histological analysis demonstrated a gradual increase in fibrosis and a decrease in cardiomyocyte volume density with age. We conclude that, although significant physiological and morphological changes occurred in heart function and structure between 12 and 39 mo of age, these changes did not likely contribute to mortality. We report reference values for cardiac function and structure in adult FBN male rats through very old age at 3-mo intervals.

Gender differences in the cardiac response to dietary conjugated linoleic acid isomers

2006 ◽  
Vol 84 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Paramjit S. Tappia ◽  
Rabban Mangat ◽  
Cindy Gabriel ◽  
Melissa R. Dent ◽  
Nina Aroutiounova ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Heart Rate ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Female Rats ◽  
Male Rats ◽  
Control Group ◽  
Ventricular Systolic Pressure ◽  
Left Ventricular Systolic Pressure

The present study was undertaken to assess the heart function, by the in vivo catheterization technique, of healthy male and female Sprague–Dawley rats fed different conjugated linoleic acid (CLA) isomers, (cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12)) individually and in combination (50:50 mix as triglyceride or fatty acids) from 4 to 20 weeks of age. Whereas the triglyceride form of the CLA isomer mix lowered the heart rate, the rate of contraction (+dP/dt) and rate of relaxation (–dP/dt), systolic and diastolic pressures, mean arterial pressure, and the left ventricular systolic pressure were higher in male rats as compared with all the other dietary groups. In contrast, there were no significant effects in the cardiac function of the female rats in response to the CLA isomer mix in triglyceride form. Whereas the heart rate, +dP/dt, and left ventricular systolic pressure were lower in male rats fed the t10,c12 CLA isomer alone, the heart rate of the female rats was higher, but the systolic pressure, +dP/dt, and mean arterial pressure were lower compared with the control group. Also, the left ventricular end-diastolic pressure was specifically higher in the female rats in response to free fatty acids-containing CLA mix. Furthermore, an additive effect of the free fatty acids-containing CLA mix was seen in the +dP/dt and –dP/dt of female rats compared with the control group. These results indicate that CLA isomers exert differential effects on heart function and suggest the need for a complete evaluation of the benefits, interactions, and potential side effects of each isomer.

Exercise- and hypertension-induced collagen changes are related to left ventricular function in rat hearts

1996 ◽  
Vol 270 (1) ◽  
pp. H151-H159 ◽  
Author(s):  
M. L. Burgess ◽  
J. Buggy ◽  
R. L. Price ◽  
F. L. Abel ◽  
L. Terracio ◽  
...  
Keyword(s):  
Heart Function ◽  
Left Ventricular ◽  
Male Rats ◽  
Heart Weight ◽  
Experimental Hypertension ◽  
Chronic Hypertension ◽  
Rat Hearts ◽  
Important Relationship ◽  
Collagen Iii ◽  
Left Ventricular Collagen

Chronic hypertension, known to affect the collagen profile of the heart, and exercise result in impaired or improved heart function, respectively. Collagen types I [alpha 1(I)2 and alpha 2(I)] and III [alpha 1(III)3] are the predominant interstitial collagens thought to influence cardiac function, and the ratio of type III to I (collagen III/I) is thought to be a significant factor in the altered relaxation observed in hypertrophy. The present study tested the hypothesis that the myocardial structure and function are different in chronically exercise-trained vs. hypertensive rat hearts. Male rats were either chronically exercised (XTr) or submitted to experimental hypertension by coarctation of the abdominal aorta (Hyp) for 10 wks. Heart rate, blood pressure, and maximal rate of fall of the left ventricular pressure (-dp/dt) were recorded during isoproterenol stimulation. Results showed that both Hyp and XTr had higher heart weight and left ventricular weight-to-body weight ratios (P < 0.05). Mean arterial pressure (MAP) was higher in Hyp and lower in XTr (P < 0.05), whereas (-dP/dt)/MAP was diminished in Hyp but enhanced in XTr. Left ventricular collagen was higher in Hyp than XTr, whereas collagen III/I was reduced in Hyp compared with XTr (P < 0.05). Scanning and transmission electron microscopy also supported an accumulation of left ventricular collagen in Hyp compared with XTr. A negative correlation was observed between collagen III/I and (-dP/dt)/ MAP (r = -0.91; P < 0.05). These results suggest an important relationship between adaptations in left ventricular collagen and the changes in diastolic function observed in both chronic hypertension and exercise cardiac stress.

scholarly journals SHP-2-Induced Activation of c-Myc Is Involved in PDGF-B-Regulated Cell Proliferation and Angiogenesis in RMECs

2020 ◽  
Vol 11 ◽  
Author(s):  
Jun Ma ◽  
Wenyi Tang ◽  
Ruiping Gu ◽  
Fangyuan Hu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Tube Formation ◽  
Proliferative Retinopathy ◽  
Cell Counting ◽  
Brdu Incorporation ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

Background: Aberrant neovascularization resulting from inappropriate angiogenic signaling is closely related to many diseases, such as cancer, cardiovascular disease, and proliferative retinopathy. Although some factors involved in regulating pathogenic angiogenesis have been identified, the molecular mechanisms of proliferative retinopathy remain largely unknown. In the present study, we determined the role of platelet-derived growth factor-B (PDGF-B), one of the HIF-1-responsive gene products, in cell proliferation and angiogenesis in retinal microvascular endothelial cells (RMECs) and explored its regulatory mechanism.Methods: Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation, tube formation, cell migration, and Western blot assays were used in our study.Results: Our results showed that PDGF-B promoted cell proliferation and angiogenesis by increasing the activity of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) in RMECs, which was attenuated by the inhibition of PDGF receptor (PDGFR) or SHP-2 knockdown. Moreover, activation of c-Myc was involved in the processes of PDGF-B/SHP-2-driven cell proliferation in RMECs. The promoting effects of PDGF-B/SHP-2 on c-Myc expression were mediated by the Erk pathway.Conclusion: These results indicate that PDGF-B facilitates cell proliferation and angiogenesis, at least in part, via the SHP-2/Erk/c-Myc pathway in RMECs, implying new potential treatment candidates for retinal microangiopathy.

scholarly journals Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 964
Author(s):  
Árpád Kovács ◽  
Melissa Herwig ◽  
Heidi Budde ◽  
Simin Delalat ◽  
Detmar Kolijn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Rat Heart ◽  
Molecular Mechanisms ◽  
Sham Group ◽  
Left Ventricular ◽  
Male Rats ◽  
Passive Stiffness ◽  
Tgf Β1

Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague–Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3–5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca2+-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-β1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-β1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper Fpassive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness; however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca2+-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca2+-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV.

scholarly journals Shenlijia Attenuates Doxorubicin-Induced Chronic Heart Failure by Inhibiting Cardiac Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xutao Sun ◽  
Yunjia Song ◽  
Ying Xie ◽  
Jieru Han ◽  
Fei Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Left Ventricular ◽  
Protein Chip ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Application of the anticancer drug doxorubicin (DOX) is restricted due to its adverse, cardiotoxic side effects, which ultimately result in heart failure. Moreover, there are a limited number of chemical agents for the clinical prevention of DOX-induced cardiotoxicity. Based on the theories of traditional Chinese medicine (TCM) on chronic heart failure (CHF), Shenlijia (SLJ), a new TCM compound, has been developed to fulfill multiple functions, including improving cardiac function and inhibiting cardiac fibrosis. In the present study, the protective effects and molecular mechanisms of SLJ on DOX-induced CHF rats were investigated. The CHF rat model was induced by intraperitoneal injection of DOX for six weeks with the cumulative dose of 15 mg/kg. All rats were then randomly divided into the control, CHF, CHF + SLJ (3.0 g/kg per day), and CHF + captopril (3.8 mg/kg per day) groups and treated for further four weeks. Echocardiography and the assessment of hemodynamic parameters were performed to evaluate heart function. A protein chip was applied to identify proteins with diagnostic values that were differentially expressed following SLJ treatment. The data from these investigations showed that SLJ treatment significantly improved cardiac function by increasing the left ventricular ejection fraction, improving the hemodynamic index, and inhibiting interstitial fibrosis. Protein chip analysis revealed that SLJ upregulated MCP-1, MDC, neuropilin-2, TGF-β3, thrombospondin, TIE-2, EG-VEGF/PK1, and TIMP-1/2/3 expressions and downregulated that of MMP-13. In addition, immunohistochemistry and western blot results further confirmed that SLJ promoted TIMP-1/2/3 and inhibited MMP-13 expression. The results of the present study suggest that SLJ was effective against DOX-induced CHF rats and is related to the improvement of heart function and ultrastructure and the inhibition of myocardial fibrosis.

scholarly journals Effect of Maturation on the Resistance of Rat Hearts Against Ischemia. Study of Potential Molecular Mechanisms

2015 ◽  
pp. S685-S696 ◽  
Author(s):  
L. GRIECSOVÁ ◽  
V. FARKAŠOVÁ ◽  
I. GÁBLOVSKÝ ◽  
V. K. M. KHANDELWAL ◽  
I. BERNÁTOVÁ ◽  
...  
Keyword(s):  
Cell Signaling ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Cellular Mechanisms ◽  
Area At Risk ◽  
Mature Adult

Reduced tolerance to ischemia/reperfusion (IR) injury has been shown in elder human and animal hearts, however, the onset of this unfavorable phenotype and cellular mechanisms behind remain unknown. Moreover, aging may interfere with the mechanisms of innate cardioprotection (preconditioning, PC) and cause defects in protective cell signaling. We studied the changes in myocardial function and response to ischemia, as well as selected proteins involved in “pro-survival” pathways in the hearts from juvenile (1.5 months), younger adult (3 months) and mature adult (6 months) male Wistar rats. In Langendorff-perfused hearts exposed to 30-min ischemia/2-h reperfusion with or without prior PC (one cycle of 5-min ischemia/5-min reperfusion), we measured occurrence of reperfusion-induced arrhythmias, recovery of contractile function (left ventricular developed pressure, LVDP, in % of pre-ischemic values), and size of infarction (IS, in % of area at risk size, TTC staining and computerized planimetry). In parallel groups, LV tissue was sampled for the detection of protein levels (WB) of Akt kinase (an effector of PI3-kinase), phosphorylated (activated) Akt (p-Akt), its target endothelial NO synthase (eNOS) and protein kinase Cε (PKCε) as components of “pro-survival” cascades. Maturation did not affect heart function, however, it impaired cardiac response to lethal IR injury (increased IS) and promoted arrhythmogenesis. PC reduced the occurrence of malignant arrhythmias, IS and improved LVDP recovery in the younger animals, while its efficacy was attenuated in the mature adults. Loss of PC protection was associated with age-dependent reduced Akt phosphorylation and levels of eNOS and PKCε in the hearts of mature animals compared with the younger ones, as well as with a failure of PC to upregulate these proteins. Aging-related alterations in myocardial response to ischemia may be caused by dysfunction of proteins involved in protective cell signaling that may occur already during the process of maturation.

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