scholarly journals Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

2017 ◽  
Vol 44 (3) ◽  
pp. 1011-1023 ◽  
Author(s):  
Hui Liu ◽  
Xibo Jing ◽  
Aiqiao Dong ◽  
Baobao Bai ◽  
Haiyan Wang
Keyword(s):  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Ros Production ◽  
Rat Cardiomyocytes ◽  
Doxorubicin Treatment ◽  
Myocardial Apoptosis

Background/Aims: Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. Methods: C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. Results: The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Conclusion: Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury.

scholarly journals Traditional Chinese Medication Qiliqiangxin Attenuates Diabetic Cardiomyopathy via Activating PPARγ

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaodong Wu ◽  
Ting Zhang ◽  
Ping Lyu ◽  
Mengli Chen ◽  
Gehui Ni ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Neonatal Rat ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Protective Mechanisms ◽  
Rat Cardiomyocytes ◽  
Induced Apoptosis ◽  
Hematoxylin Eosin

Background: Diabetic cardiomyopathy is the primary complication associated with diabetes mellitus and also is a major cause of death and disability. Limited pharmacological therapies are available for diabetic cardiomyopathy. Qiliqiangxin (QLQX), a Chinese medication, has been proven to be beneficial for heart failure patients. However, the role and the underlying protective mechanisms of QLQX in diabetic cardiomyopathy remain largely unexplored.Methods: Primary neonatal rat cardiomyocytes (NRCMs) were treated with glucose (HG, 40 mM) to establish the hyperglycemia-induced apoptosis model in vitro. Streptozotocin (STZ, 50 mg/kg/day for 5 consecutive days) was intraperitoneally injected into mice to establish the diabetic cardiomyopathy model in vivo. Various analyses including qRT-PCR, western blot, immunofluorescence [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining] histology (hematoxylin–eosin and Masson's trichrome staining), and cardiac function (echocardiography) were performed in these mice. QLQX (0.5 μg/ml in vitro and 0.5 g/kg/day in vivo) was used in this study.Results: QLQX attenuated hyperglycemia-induced cardiomyocyte apoptosis via activating peroxisome proliferation-activated receptor γ (PPARγ). In vivo, QLQX treatment protected mice against STZ-induced cardiac dysfunction and pathological remodeling.Conclusions: QLQX attenuates diabetic cardiomyopathy via activating PPARγ.

scholarly journals CTRP5-Overexpression Attenuated Ischemia-Reperfusion Associated Heart Injuries and Improved Infarction Induced Heart Failure

2020 ◽  
Vol 11 ◽  
Author(s):  
Meng Peng ◽  
Yuan Liu ◽  
Xiang-qin Zhang ◽  
Ya-wei Xu ◽  
Yin-tao Zhao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Related Protein ◽  
Rat Cardiomyocytes ◽  
Knock Out ◽  
Cardiac Functions

Aims: C1q/tumor necrosis factor (TNF)-related protein 5 (CTRP5) belongs to the C1q/TNF-α related protein family and regulates glucose, lipid metabolism, and inflammation production. However, the roles of CTRP5 in ischemia/reperfusion (I/R) associated with cardiac injuries and heart failure (HF) needs to be elaborated. This study aimed to investigate the roles of CTRP5 in I/R associated cardiac injuries and heart failure.Materials and Methods: Adeno-associated virus serum type 9 （AAV9）vectors were established for CTRP5 overexpression in a mouse heart (AAV9-CTRP5 mouse). AAV9-CTRP5, AMPKα2 global knock out （AMPKα2−/−）and AAV9-CTRP5+ AMPKα2−/− mice were used to establish cardiac I/R or infarction associated HF models to investigate the roles and mechanisms of CTRP5 in vivo. Isolated neonatal rat cardiomyocytes (NRCMS) transfected with or without CTRP5 adenovirus were used to establish a hypoxia/reoxygenation (H/O) model to study the roles and mechanisms of CTRP5 in vitro.Key Findings: CTRP5 was up-regulated after MI but was quickly down-regulated. CTRP5 overexpression significantly decreased I/R induced IA/AAR and cardiomyocyte apoptosis, and attenuated infarction area, and improved cardiac functions. Mechanistically, CTRP5 overexpression markedly increased AMPKα2 and ACC phosphorylation and PGC1-α expression but inhibited mTORC1 phosphorylation. In in vitro experiments, CTRP5 overexpression could also enhance AMPKα2 and ACC phosphorylation and protect against H/O induced cardiomyocytes apoptosis. Finally, we showed that CTPR5 overexpression could not protect against I/R associated cardiac injuries and HF in AMPKα2−/− mice.Significance: CTRP5 overexpression protected against I/R induced mouse cardiac injuries and attenuated myocardial infarction induced cardiac dysfunction by activating the AMPKαsignaling pathway.

scholarly journals Resveratrol Inhibits Ischemia-Induced Myocardial Senescence Signals and NLRP3 Inflammasome Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Hong Feng ◽  
Shan-qi Mou ◽  
Wen-jing Li ◽  
Nan Zhang ◽  
Zi-ying Zhou ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Sirtuin 1 ◽  
Neonatal Rat ◽  
Tunel Staining ◽  
Mouse Heart ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Rat Cardiomyocytes

Aims. The aim of this study was to investigate whether resveratrol (RSV) could ameliorate ischemia- and hypoxia-associated cardiomyocyte apoptosis and injury via inhibiting senescence signaling and inflammasome activation. Materials and Methods. Mice were treated with RSV by gastric tube (320 mg/kg/day) or vehicle one week before left coronary artery ligation or sham surgery until the end of the experiments. After pressure–volume loop analysis, mouse hearts were harvested for histopathological (including PSR, TTC, TUNEL staining, immunohistochemistry, and immunofluorescence) and molecular analysis by western blotting and RT-PCR. In addition, neonatal rat cardiomyocytes (NRCMs), cardiac fibroblasts (CFs), and macrophages were isolated for in vitro experiments. Key Findings. RSV treatment decreased mortality and improved cardiac hemodynamics. RSV inhibited the expression of senescence markers (p53, p16, and p19), inflammasome markers (NLRP3 and Cas1 p20), and nuclear translocation of NF-κB, hence alleviating infarction area, fibrosis, and cell apoptosis. RSV also inhibited expression of interleukin- (IL-) 1β, IL-6, tumor necrosis factor-α, and IL-18 in vivo. In in vitro experiment, RSV prevented hypoxia-induced NRCM senescence and apoptosis. After inhibition of sirtuin 1 (Sirt1) by EX27, RSV failed to inhibit p53 acetylation and expression. Moreover, RSV could inhibit expression of NLRP3 and caspase 1 p20 in NRCMs, CFs, and macrophages, respectively, in in vitro experiments. Significance. Our findings revealed that RSV protected against ischemia-induced mouse heart injury in vivo and hypoxia-induced NRCM injury in vitro via regulating Sirt1/p53-mediated cell senescence and inhibiting NLRP3-mediated inflammasome activation.

Abstract 123: Erythropoietin Enhances Abundance of Cardiomyogenic Precursors in vitro and in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Maria Patapia Zafeiriou ◽  
Claudia Noack ◽  
Bernhard Unsoeld ◽  
Michael Didie ◽  
Ali El-Armouche ◽  
...  
Keyword(s):  
Adult Mouse ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Rat Cardiomyocytes ◽  
Adult Heart ◽  
Cell Pool ◽  
Epor Expression

Recent data suggest that erythropoietin (Epo) can improve cardiac function following ischemia reperfusion injury. We found EpoR to be prominently expressed in embryonic rather than adult mouse heart. In the latter EpoR expression was confined to interstitial cells. We isolated the non-myocyte fraction of adult mouse hearts by enzymatic digestion and straining (pore size: 30 µm) and found a 4-fold higher EpoR expression compared to unselected cardiac cells (n=3). Flow cytometry (FC) revealed that 24±3% of this heterogeneous cell pool expressed EpoR (n=3) and 11±2% co-expressed αMHC. Half of the αMHC+ cells stained positive for Ki67, consistent with FC showing that 49±7% αMHC+/EpoR+ cells were in S and G2 phase (n=3; vs. 13±3% in αMHC-/EpoR-; n=3). Interestingly, co-culture with neonatal rat cardiomyocytes yielded EGFP+ cardiomyocyte-like cells. Since αMHC+ proliferated and differentiated in vitro we termed them cardiomyogenic precursors (CMPs). Epo treatment of the non-myocyte pool enhanced Akt phosphorylation (n=6/group) and increased CMP abundance in vitro (2-fold; n=3). Cell cycle arrest abrogated the aforementioned effect, suggesting that Epo influenced CMP proliferation. Finally, we tested the potential of Epo to protect against ischemia by enhancing CMP numbers in a model of myocardial infarction (MI). Following MI mice were treated twice with 2,000 U/kg Epo (i.p.). Ten weeks post MI echocardiography revealed blunted myocardial deterioration in mice receiving Epo (ΔEF=-11.18%, n=5) compared to control (ΔEF=-20.82%, n=6). FC revealed an enhanced αMHC+/cTnT+ cell pool in the Epo treated group (20.3±1.9% vs. 10.6±2.3% in control, n=8/6) 4 weeks post MI. In conclusion, we found that EpoR is expressed in a putative cardiomyogenic precursor cell pool in the adult heart. CMPs appear to proliferate in vitro and in vivo; with further enhanced proliferation under Epo administration. This may contribute to Epo mediated protection after MI and highlights the therapeutic effect of Epo upon ischemic cardiac injury. Whether these cells remain from embryogenesis or just constitute an immature myocyte population in the adult heart deriving from cardiomyocyte dedifferentiation needs to be further investigated.

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽  
2021 ◽  
Vol 106 (3-4) ◽  
pp. 189-201
Author(s):  
Shigang Qiao ◽  
Wen-jie Zhao ◽  
Huan-qiu Li ◽  
Gui-zhen Ao ◽  
Jian-zhong An ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Neonatal Rat ◽  
Ligand Docking ◽  
Autophagic Flux ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

(-)-Epigallocatechin Gallate Promotes MicroRNA 145 Expression against Myocardial Hypoxic Injury through Dab2/Wnt3a/β-catenin

2020 ◽  
Vol 48 (02) ◽  
pp. 341-356
Author(s):  
Chiu-Mei Lin ◽  
Wei-Jen Fang ◽  
Bao-Wei Wang ◽  
Chun-Ming Pan ◽  
Su-Kiat Chua ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Real Time ◽  
Real Time Pcr ◽  
Myocardial Infarct ◽  
Epigallocatechin Gallate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Rat Cardiomyocytes

MicroRNA 145 (miR-145) is a critical modulator of cardiovascular diseases. The downregulation of myocardial miR-145 is followed by an increase in disabled-2 (Dab2) expression in cardiomyocytes. (-)-epigallocatechin gallate (EGCG) is a flavonoid that has been evaluated extensively due to its diverse pharmacological properties including anti-inflammatory effects. The aim of this study was to investigate the cardioprotective effects of EGCG under hypoxia-induced stress in vitro and in vivo. The hypoxic insult led to the suppression of miR-145 expression in cultured rat cardiomyocytes in a concentration-dependent manner. Western blotting and real-time PCR were performed. In rat myocardial infarction study, in situ hybridization, and immunofluorescent analyses were adopted. The western blot and real-time PCR data revealed that hypoxic stress with 2.5% O2 suppressed the expression of miR-145 and Wnt3a/[Formula: see text]-catenin in cultured rat cardiomyocytes but augmented Dab2. Treatment with EGCG attenuated Dab2 expression, but increased Wnt3a and [Formula: see text]-catenin in hypoxic cultured cardiomyocytes. Following in vivo myocardial infarction (MI) study, the data revealed the myocardial infarct area reduced by 48.5%, 44.6%, and 48.5% in EGCG (50[Formula: see text]mg/kg) or miR-145 dominant or Dab2 siRNA groups after myocardial infarction for 28 days, respectively. This study demonstrated that EGCG increased miR-145, Wnt3a, and [Formula: see text]-catenin expression but attenuated Dab2 expression. Moreover, EGCG ameliorated myocardial ischemia in vivo. The novel suppressive effect was mediated through the miR-145 and Dab2/Wnt3a/[Formula: see text]-catenin pathways.

scholarly journals Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

2020 ◽  
Vol 21 (9) ◽  
pp. 3359
Author(s):  
Zoltán Giricz ◽  
András Makkos ◽  
Rolf Schreckenberg ◽  
Jochen Pöling ◽  
Holger Lörchner ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Common Mechanism ◽  
Structural Adaptation ◽  
Infarct Zone ◽  
Rat Cardiomyocytes ◽  
Ischemic Conditioning

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species.

scholarly journals Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Changsheng Nai ◽  
Haochen Xuan ◽  
Yingying Zhang ◽  
Mengxiao Shen ◽  
Tongda Xu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Signaling Pathway ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Myocardial Infarct Size ◽  
Akt Signaling Pathway ◽  
Cardioprotective Effects

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

scholarly journals Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1309
Author(s):  
Sandra Funcke ◽  
Tessa R. Werner ◽  
Marc Hein ◽  
Bärbel M. Ulmer ◽  
Arne Hansen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemia Reperfusion ◽  
Heart Tissue ◽  
Contractile Force ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Engineered Heart Tissue ◽  
Hypoxia Reoxygenation

Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** p = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [d-Ala2, d-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, p = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.

Mechanical stimulation of organogenic cardiomyocyte growth in vitro

1996 ◽  
Vol 270 (5) ◽  
pp. C1284-C1292 ◽  
Author(s):  
H. H. Vandenburgh ◽  
R. Solerssi ◽  
J. Shansky ◽  
J. W. Adams ◽  
S. A. Henderson
Keyword(s):  
Mechanical Load ◽  
Mechanical Stretch ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Heart Cells ◽  
Mechanical Stimuli ◽  
Rat Cardiomyocytes ◽  
Morphological Alterations

Adherent cultures of neonatal rat cardiomyocytes were subjected to progressive, unidirectional lengthening for 2-4 days in serum-containing medium. This mechanical stretch (25% increase in initial length each day) simulates the eccentric mechanical load placed on in vivo heart cells by increases in postnatal blood pressure and volume. The in vitro mechanical stimuli initiated a number of morphological alterations in the confluent cardiomyocyte population which were similar to those occurring during in vivo heart growth. These include cardiomyocyte organization into parallel arrays of rod-shaped cells, increased cardiomyocyte binucleation, and cardiomyocyte hypertrophy by longitudinal cell growth. Stretch stimulated DNA synthesis in the noncardiomyocyte population but not in the cardiomyocytes. Myosin heavy chain (MHC) content increased 62% over 4 days of stretch and included increased accumulation of both fetal beta-MHC and adult alpha-MHC isoforms. This new model of stretch-induced cardiomyocyte hypertrophy may assist in examining some of the complex mechanogenic growth processes that occur in the rapidly enlarging neonatal heart.

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