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Thomas Eschenhagen

Publications and source records attributed to Thomas Eschenhagen.

At least 19 recordsLinked to original sources
PubMed2004

Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts.

OBJECTIVE: The protein phosphatase inhibitor-1 (I-1) is a highly specific and potent inhibitor of type 1 phosphatases (PP1) that is active only in its protein kinase A (PKA)-phosphorylated form. I-1 ablation decreases, I-1 overexpression sensitizes beta-adrenergic signaling in the heart. It is controversial whether I-1 expression is altered in human heart failure (HF), likely because its detection in heart is difficult due to its low abundance. METHODS AND RESULTS: I-1 was >500-fold enriched from left ventricular myocardium (LVM) from patients with terminal HF (n=16) and non-failing controls (NF, n=5) and quantified with an affinity-purified I-1 and a I-1 phosphospecific antiserum. In non-failing I-1 protein levels amounted to 126 fmol/mg protein. In failing hearts, I-1 protein levels were reduced by 58% and I-1 phosphorylation by 77% (P<0.001 vs. NF). I-1 phosphorylation correlated well with serine-16 phosphorylation of phospholamban (PLB) in the same hearts (P<0.001). In contrast, PLB, troponin I (TnI) and PP1 protein and TnI phosphorylation levels did not differ between HF and NF. CONCLUSIONS: The results suggest that the reduction in I-1 protein and phosphorylation in failing human hearts leads to increased phosphatase activity which in turn may result in reduced phosphorylation of cardiac proteins such as PLB.

Adult↗
PubMed2004

Engineered heart tissue for regeneration of diseased hearts.

Cardiac tissue engineering aims at providing contractile heart muscle constructs for replacement therapy in vivo. At present, most cardiac tissue engineering attempts utilize heart cells from embryonic chicken and neonatal rats and scaffold materials. Over the past years our group has developed a novel technique to engineer collagen/matrigel-based cardiac muscle constructs, which we termed engineered heart tissue (EHT). EHT display functional and morphological properties of differentiated heart muscle and can be constructed in different shape and size from collagen type I, extracellular matrix proteins (Matrigel((R))), and heart cells from neonatal rats and embryonic chicken. First implantation studies in syngeneic Fischer 344 rats provided evidence of EHT survival and integration in vivo. This review will focus on our experience in tissue engineering of cardiac muscle. Mainly, EHT construction, matrix requirements, potential applications of different cell types including stem cells, and our first implantation experiences will be discussed. Despite many critical and unresolved questions, we believe that cardiac tissue engineering in general has an interesting perspective for the replacement of malfunctioning myocardium and reconstruction of congenital malformations.

Animals↗
PubMed2003

Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure.

Heart failure is accompanied by stereotypic alterations in cardiac gene expression. These changes are most likely secondary in the pathogenesis and can be viewed as protective, e.g. as energy-saving mechanisms, but at the same time, they aggravate contractile dysfunction and the deficit of failing cardiac myocytes to respond to altered hemodynamic needs. One of the best-studied, paradigmatic examples of this dichotomy is heterologous desensitization of the cardiac adenylyl cyclase (AC) signaling pathway. It protects against detrimental consequences of the excessive adrenergic drive, but it also blunts the most powerful inotropic support of the heart. Desensitization is associated with downregulation of beta-adrenergic receptors, increased beta-adrenoceptor kinases and increased inhibitory G protein alpha-subunits, G(alphai). Whereas a causative role of the former is generally accepted, the role of the increase in G(alphai) has remained controversial for many years. The present article summarizes early and novel findings that, in the view of the authors, provide solid evidence for G(alphai) to play an important role in the adaptation of cardiac AC to various pathophysiological conditions.

Adenylyl Cyclases↗
PubMed2003

What is the role of beta-adrenergic signaling in heart failure?

This review addresses open questions about the role of beta-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three beta-adrenergic receptor subtypes-beta1, beta2, and, at least in some species, beta3. The beta1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The beta2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the beta1 subtype. In heart failure, the sympathetic system is activated, cardiac beta-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, beta-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the beta-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.

Adrenergic beta-Antagonists↗
PubMed2003

Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase.

OBJECTIVE: The cardiac ankyrin repeat protein (CARP), a nuclear transcription co-factor that negatively regulates cardiac gene expression, is increased in human heart failure and in animal models of cardiac hypertrophy. The mechanism by which CARP expression is regulated and the consequences of CARP overexpression on cardiac contractility are unknown. METHODS AND RESULTS: Compared to vehicle treated controls, 4-day treatment of male Wistar rats with the beta-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) induced hypertrophy and significantly increased CARP mRNA and CARP protein levels in left ventricles. The signalling pathways were investigated in more detail in isolated neonatal rat cardiomyocytes. Treatment of cells with isoprenaline (1 micromol/l) caused a significant increase in CARP mRNA and protein by approximately 50%. Combined beta(1)- and beta(2)-adrenoceptor blockade, inhibition of protein kinase A (PKA; Rp-cAMPS, 100 micromol/l), and inhibition of calmodulin-dependent protein kinases (CaMK; KN-62, 10 micromol/l) completely reversed the effects of isoprenaline. To examine the consequences of CARP overexpression on contractile function, an adenovirus encoding human CARP as well as a control virus were constructed. Although the basal force of contraction was not different, contractile response to Ca(2+) and isoprenaline was significantly diminished in engineered heart tissue infected with the recombinant adenovirus that carries the CARP gene (Ad.CARP). CONCLUSIONS: Our study provides the first evidence that overexpression of CARP, which is thought to act as a transcriptional co-repressor, may deteriorate contractile function of the heart tissue. Furthermore, beta-adrenoceptor stimulation and activation of PKA and CaMK have been identified as mechanisms that induce expression of CARP in cardiomyocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2003

Overexpression of wild-type Galpha(i)-2 suppresses beta-adrenergic signaling in cardiac myocytes.

The role of Galpha(i)-2 overexpression in desensitization of beta-adrenergic signaling in heart failure is controversial. An adenovirus-based approach was used to investigate whether overexpression of Galpha(i)-2 impairs beta-adrenergic stimulation of adenylyl cyclase (AC) activity and cAMP levels in neonatal rat cardiac myocytes (NRCM) and cell shortening of adult rat ventricular myocytes (ARVM). Infection of NRCM with Ad5Galpha(i)-2 increased Galpha(i)-2 by 50-600% in a virus dose-dependent manner. Overexpression was paralleled by suppression of GTP- and isoprenaline-stimulated AC by 10-72% (P<0.001) in a PTX-sensitive manner. Isoprenaline-stimulated shortening of Ad5Galpha(i)-2-infected ARVM was attenuated by 34% (P<0.01). Ad5Galpha(i)-2/GFP (Galpha(i)-2, green fluorescent protein; bicistronic) was constructed to monitor transfection homogeneity and target Galpha(i)-2 overexpression to levels found in heart failure. At Galpha(i)-2 levels of 93% above control, isoprenaline-stimulated AC activity and cAMP levels were reduced by 17% and 40% (P<0.02), respectively. Beta1- and beta2-adrenergic stimulation was reduced similarly. Our results suggest that (a) the Galpha(i)-2 system exhibits tonic inhibition of stimulated AC in cardiac myocytes, (b) Galpha(i)-2-mediated inhibition is concentration-dependent and occurs at Galpha(i)-2 levels seen in heart failure, and (c) Galpha(i)-2-mediated inhibition affects both beta1- and beta2-adrenergic stimulation of AC. The data argue for an important, independent role of the Galpha(i)-2 increase in heart failure.

Adenoviridae↗
PubMed2003

Evidence for protein phosphatase inhibitor-1 playing an amplifier role in beta-adrenergic signaling in cardiac myocytes.

The protein phosphatase inhibitor-1 (PPI-1) inhibits phosphatase type-1 (PP1) only when phosphorylated by protein kinase A and could play a pivotal role in the phosphorylation/dephosphorylation balance. Rat cardiac PPI-1 was cloned by reverse transcriptase-polymerase chain reaction, expressed in Eschericia coli, evaluated in phosphatase assays, and used to generate an antiserum. An adenovirus was constructed encoding PPI-1 and green fluorescent protein (GFP) under separate cytomegalovirus promotors (AdPPI-1/GFP). A GFP-only virus (AdGFP) served as control. Engineered heart tissue (EHT) from neonatal rat cardiomyocytes and adult rat cardiac myocytes (ARCMs) were used as model systems. PPI-1 expression was determined in human ventricular samples by Northern blots. Compared with AdGFP, AdPPI-1/GFP-infected neonatal rat cardiomyocytes displayed a 73% reduction in PP1 activity. EHTs infected with AdPPI-1/GFP exhibited a fivefold increase in isoprenaline sensitivity. AdPPI-1/GFP-infected ARCMs displayed enhanced cell shortening as well as enhanced phospholamban phosphorylation when stimulated with 1 nM isoprenaline. PPI-1 mRNA levels were reduced by 57+/-12% in failing hearts with dilated and ischemic cardiomyopathy (n=8 each) compared with nonfailing hearts (n=8). In summary, increased PPI-1 expression enhances myocyte sensitivity to isoprenaline, indicating that PPI-1 acts as an amplifier in beta-adrenergic signaling. Decreased PPI-1 in failing human hearts could participate in desensitization of the cAMP pathway.

Adenoviridae↗
PubMed2003

Differential coupling of m-cholinoceptors to Gi/Go-proteins in failing human myocardium.

Muscarinic acetylcholine receptors (mAChRs) mediate their main cardiac effects via pertussis toxin-sensitive G-proteins. Physiological effects differ considerably between atrium and ventricle, and it is unknown to which extent these differences derive from selective receptor-G-protein coupling or further downstream events. We have characterized specific coupling between mAChRs and Gi/Go-protein isoforms in atrial and ventricular myocardium by agonist-dependent photoaffinity labeling with [(32)P]azidoanilido GTP (aaGTP) and immunoprecipitation in sarcolemmal membranes from terminally failing human hearts. The total amount of mAChRs, as determined by specific binding of [(3)H]QNB, was significantly higher in right-atrial (RA +/- SEM, 959 +/- 68 fmol/mg, n = 4) than in left-ventricular membranes (LV, 582 +/- 53 fmol/mg, n = 6). Standardized immunoblots revealed that Gialpha-2 was the predominant subtype in both regions. A 40-kDa splice variant of Goalpha (Goalpha-1 and/or Goalpha-3) was almost exclusively detectable in RA. Levels of Gialpha-3 and a 39-kDa splice variant of Goalpha (Goalpha-2) were also higher in RA. Basal aaGTP binding was higher in RA than in LV for all Gialpha/Goalpha subtypes. The carbachol (10 micromol/l)-induced increase in aaGTP binding was significantly higher in RA than in LV for Goalpha-1/3 (336 +/- 95% of LV, n = 4) and for Gialpha-3 (211 +/- 83%), lower for Gialpha-2 (42 +/- 5%), and was similar in both regions for Goalpha-2 (130 +/- 62%). The differential coupling of mAChRs in human RA and LV suggests that the initiation of different physiological responses to mAChR stimulation starts with signal sorting at the receptor-G-protein level.

Acetylcholine↗
PubMed2003

Cardiac tissue engineering for replacement therapy.

Cell therapy is a new concept to repair diseased organs. For patients with myocardial infarction, heart failure, and congenital heart diseases cell based therapies might represent a potential cure. The field can be subdivided into two principally different approaches: (1) Implantation of isolated cells and (2) implantation of in vitro engineered tissue constructs. This review will focus on the latter approach. Cardiac tissue engineering comprises the fields of material sciences and cell biology. In general, scaffold materials such as gelatin, collagen, alginate, or synthetic polymers and cardiac cells are utilized to reconstitute tissue-like constructs in vitro. Ideally, these constructs display properties of native myocardium such as coherent contractions, low diastolic tension, and syncytial propagation of action potentials. To be applicable for surgical repair of diseased myocardium engineered tissue constructs should have the propensity to integrate and remain contractile in vivo. Size and mechanical properties of engineered constructs are critical for surgical repair of large tissue defects. Successful application of tissue engineering in men will depend on the utilization of an autologous or non-immunogeneic cell source and scaffold material to avoid life long immunosuppression. This review will give an overview of recent approaches in cardiac tissue engineering and its first applications in vivo. We will discuss materials and cell sources for cardiac tissue engineering. Further, principle obstacles will be addressed. Cardiac tissue engineering for replacement therapy has an intriguing perspective, but is in its early days. Its true value remains to be thoroughly evaluated.

Animals↗
PubMed2003

Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice.

Heme oxygenase-1 (HO-1), a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin, and iron, has previously been shown to protect grafts from ischemia/reperfusion injury and rejection. Here we investigated the protective potential of HO-1 in 5 models of immune-mediated liver injury. We found that up-regulation of endogenous HO-1 by cobalt-protoporphyrin-IX (CoPP) protected mice from apoptotic liver damage induced by anti-CD95 antibody (Ab) or d-galactosamine in combination with either anti-CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor alpha (TNF-alpha). HO-1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice from caspase-3-independent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO-1 by adenoviral gene transfer resulted in protection from apoptotic liver injury, whereas inhibition of HO-1 enzymatic activity by tin-protoporphyrin-IX (SnPP) abrogated the protective effect. HO-1-mediated protection seems to target parenchymal liver cells directly because CoPP treatment protected isolated primary hepatocytes from anti-CD95-induced apoptosis in vitro. Furthermore, depletion of Kupffer cells (KCs) did not interfere with the protective effect in vivo. Exogenous CO administration or treatment with the CO-releasing agent methylene chloride mimicked the protective effect of HO-1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not. In conclusion, HO-1 is a potent protective factor for cytokine- and CD95-mediated apoptotic liver damage. Induction of HO-1 might be of a therapeutic modality for inflammatory liver diseases.

Adenoviridae↗
PubMed2002

Cardiac grafting of engineered heart tissue in syngenic rats.

BACKGROUND: Cell grafting has emerged as a novel approach to treat heart diseases refractory to conventional therapy. We hypothesize that survival and functional and electrical integration of grafts may be improved by engineering cardiac tissue constructs in vitro before grafting. METHODS AND RESULTS: Engineered heart tissue (EHT) was reconstituted by mixing cardiac myocytes from neonatal Fischer 344 rats with liquid collagen type I, matrigel, and serum-containing culture medium. EHTs were designed in circular shape (inner/outer diameter: 8/10 mm; thickness: 1 mm) to fit around the circumference of hearts from syngenic rats. After 12 days in culture and before implantation on uninjured hearts, contractile function of EHT was measured under isometric conditions. Baseline twitch tension amounted to 0.34+/-0.03 mN (n=33) and was stimulated by Ca(2+) and isoprenaline to 200+/-12 and 185+/-10% of baseline values, respectively. Despite utilization of a syngenic model immunosuppression (mg/kg BW: azathioprine 2, cyclosporine A 5, methylprednisolone 2) was necessary for EHT survival in vivo. Echocardiography conducted 7, 14, and 28 days after implantation demonstrated no change in left ventricular function compared with pre-OP values (n=9). Fourteen days after implantation, EHTs were heavily vascularized and retained a well organized heart muscle structure as indicated by immunolabeling of actinin, connexin 43, and cadherins. Ultrastructural analysis demonstrated that implanted EHTs surpassed the degree of differentiation reached before implantation. Contractile function of EHT grafts was preserved in vivo. CONCLUSIONS: EHTs can be employed for tissue grafting approaches and might serve as graft material to repair diseased myocardium.

Animals↗
PubMed2002

Augmented expression of cardiotrophin-1 in failing human hearts is accompanied by diminished glycoprotein 130 receptor protein abundance.

BACKGROUND: Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, is a potent inducer of cardiomyocyte hypertrophy that prolongs myocyte survival. Although cardiac CT-1 gene expression is known to be upregulated in some animal models of congestive heart failure, the activation state of the CT-1 system in patients with congestive heart failure is unknown. METHODS AND RESULTS: This study was designed to determine left ventricular expression of CT-1 and its glycoprotein 130 (gp130)/leukemia inhibitory factor receptor complex in human end-stage heart failure due to ischemic and dilated cardiomyopathy. In addition, we investigated the activation state of signal transducer and activator of transcription 3 (STAT3), the downstream effector of gp130 signaling. In the failing left ventricular myocardium, expression levels of CT-1 mRNA and protein were significantly increased by 142% and 68%, respectively, compared with non-failing donor hearts. Immunohistochemistry confirmed the increased expression of CT-1 in cardiac myocytes. Although gp130 gene expression was increased by 91% (P<0.001), gp130 protein abundance was significantly diminished by 34% in the failing myocardium. In contrast, leukemia inhibitory factor receptor and suppressor of cytokine signaling-3 protein concentrations were not changed. In addition, the ratio of activated tyrosine phosphorylated STAT3 to total STAT3 was not significantly altered in failing hearts compared with non-failing controls. CONCLUSIONS: Our data suggest that gp130 receptor downregulation balances enhanced CT-1 expression in human heart failure and thereby inhibits excessive activation of the gp130 signaling pathway.

Antigens, CD↗
PubMed2002

Intracellular beta-blockade: overexpression of Galpha(i2) depresses the beta-adrenergic response in intact myocardium.

OBJECTIVE: Increased levels of inhibitory G proteins have been observed in heart failure, but their physiological relevance in mediating the reduced beta-adrenergic response is largely unknown. METHODS: To evaluate the functional consequences of Galpha(i2) overexpression, we studied myocardial contraction in intact isometric contracting cardiac rabbit trabeculae and isolated myocytes after adenovirus-mediated gene transfer of Galpha(i2). RESULTS: Neither Galpha(i2) nor lacZ (control) overexpression altered baseline contractile force. After 72 h of continuous contractions, developed force (F(dev)) increased after addition of 1 microM isoproterenol by 28.5+/-9.7 mN/mm(2) in the control group, which was unchanged from the initial response at t=0 h (23.7+/-3.8 mN/mm(2)). In sharp contrast, in preparations transfected with AdGalpha(i2), the response to isoproterenol was significantly attenuated (5.9+/-2.0 vs. 27.6+/-4.2 mN/mm(2), t=72 vs. 0 h, respectively, P<0.01). In a primary culture of transfected isolated myocytes from a nearly identical baseline, isoproterenol increased cell shortening by 3.1+/-0.6% in the lacZ transfected myocytes, but only by 1.3+/-0.5% in Galpha(i2) transfected myocytes (t=72 h, P<0.01). In Galpha(i2) transfected myocytes, pertussis toxin restored beta-adrenergic responsiveness, indicating specificity of attenuation by the transgene. CONCLUSIONS: Overexpression of Galpha(i2) attenuates the positive inotropic effects of beta-adrenergic stimulation in myocardium. In addition, the method we developed allows investigation of a causal link between altered protein expression and subsequent alterations in contractile function in a physiological relevant in vitro manner.

Adenoviridae↗
PubMed2002

Specific beta(2)AR blocker ICI 118,551 actively decreases contraction through a G(i)-coupled form of the beta(2)AR in myocytes from failing human heart.

BACKGROUND: We have observed direct (noncatecholamine-blocking) negative inotropic effects of the selective beta(2)-adrenoceptor (AR) antagonist ICI 118,551 in myocytes from failing human ventricle. In this study we characterize the effect in parallel in human myocytes and in myocytes from animal models where beta(2)ARs or G(i) proteins are overexpressed. METHODS AND RESULTS: Enzymatically isolated, superfused ventricular myocytes were exposed to betaAR agonists and antagonists/inverse agonists, and contraction amplitude was measured. ICI 118,551 decreased contraction in ventricular myocytes from failing human hearts by 45.3+/-4.1% (n=20 hearts/31 myocytes, P<0.001) but had little effect in nonfailing hearts (4.9+/-4%, n=5 myocytes/3 hearts). Effects were significantly larger in patients classified as end-stage. Transgenic mice with high beta(2)AR number and increased G(i) levels had normal basal contractility but showed a similar negative inotropic response to ICI 118,551. Overexpression of human beta(2)AR in rabbit myocytes using adenovirus potentiated the negative inotropic effect of ICI 118,551. In human, rabbit, and mouse myocytes, the negative inotropic effects were blocked after treatment of cells with pertussis toxin to inactivate G(i), and overexpression of G(i)alpha(2) induced the effect de novo in normal rat myocytes. CONCLUSIONS: We hypothesize that ICI 118,551 binding directs the beta(2)AR to a G(i)-coupled form and away from the G(s)-coupled form (ligand-directed trafficking). ICI 118,551 effectively acts as an agonist at the G(i)-coupled beta(2)AR, producing a direct negative inotropic effect. Conditions where beta(2)ARs are present and G(i) is raised (failing human heart, TGbeta(2) mouse heart) predispose to the appearance of the negative inotropic effect.

Adrenergic beta-2 Receptor Antagonists↗
PubMed2002

Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure.

The technique of representational difference analysis of cDNA has been applied to screen for differentially expressed genes in a canine model of pacing-induced heart failure. We identified the canine homolog of the cardiac ankyrin repeat protein (CARP) which has been shown to be involved in the regulation of the transcription of cardiac genes. To confirm the significance for human heart failure, cardiac tissue specimens obtained from non-failing donor hearts and from explanted hearts from patients with end-stage heart failure were investigated. CARP mRNA and protein levels were markedly increased in failing left ventricles. Interestingly, alterations in CARP expression were restricted to ventricular tissue and were not observed in atria. Fractionation experiments revealed that CARP was expressed predominantly in the nuclei consistent with the proposed function of CARP as a modulator of transcription. Together, these findings raise the possibility that augmented ventricular CARP expression may play a role in the pathogenesis of human heart failure.

Adult↗
PubMed2002

Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats.

OBJECTIVE: To characterize the cardiac angiotensin and endothelin (ET) system in compensated left ventricular hypertrophy due to long standing arterial hypertension and to assess the role of angiotensin and ET converting enzymes in mediating the observed changes of angiotensin and ET levels, respectively. METHODS: We studied the left ventricular renin-angiotensin system (RAS) and ET system in 20-week-old male transgenic hypertensive TG(mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension. Age-matched Sprague-Dawley rats served as controls. RESULTS: TG(mREN2)27 rats exhibited left ventricular hypertrophy without signs of congestion. Transgene overexpression led to an activation of the tissue RAS with increased angiotensin II levels in spite of unchanged angiotensin converting enzyme (ACE) activity and ACE mRNA levels. ET-1 production was markedly increased in TG(mREN2)27 rats indicating that the ET-system was activated. Cardiac ET-1 in TG(mREN2)27 originated most likely from increased preproET-1 production because preproET-1 mRNA levels were increased but ET converting enzyme gene expression and activity were unchanged. Furthermore, ET-1 binding sites were significantly increased in TG(mREN2)27 rats without changes in K(D) values and ET(A)/ET(B) receptor ratios. ET(A) receptor gene expression was not altered whereas ET(B) receptor mRNA levels were up-regulated twofold in TG(mREN2)27 rats suggesting that ET(A) and ET(B) receptor expression may be regulated differentially. CONCLUSIONS: Cardiac ET and angiotensin systems are co-activated in compensated cardiac hypertrophy before onset of heart failure, and thus may be involved in the mechanism by which cardiac remodelling and progression of left ventricular dysfunction occur in TG(mREN2)27 rats.

Angiotensin II↗
PubMed2002

3D engineered heart tissue for replacement therapy.

Myocardial infarction results in irreversible loss of cardiac myocytes and heart failure. Tissue or cell grafting offers the prospect of reintroducing contractile elements into impaired hearts. However, implanted cardiac myocytes remain physically and electrically isolated from the viable myocardium. Accordingly, the proof of increased contractile function attributable specifically to cell grafting procedures is sparse. Over the last few years, we have developed a new method to generate three-dimensional engineered heart tissue (EHTs) in vitro from embryonic chick or neonatal rat cardiac myocytes. EHTs comprise functional and morphological properties of intact myocardium. We hypothesized that EHTs, preformed in vitro into suitable geometric forms, represent appropriate graft material for in vivo tissue repair with advantages over isolated cells. Herein we describe initial results from implantation experiments of EHTs in the peritoneum of Fisher 344 rats. EHTs survived for at least 14 days, maintained a network of differentiated cardiac myocytes, and were strongly vascularized. Thus, the present study provides the first evidence for the general feasibility of EHTs as material for a novel tissue replacement approach.

Animals↗