Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

2011 ◽  
Vol 301 (5) ◽  
pp. H2061-H2072 ◽  
Author(s):  
Takayuki Shimazu ◽  
Hajime Otani ◽  
Kei Yoshioka ◽  
Masanori Fujita ◽  
Toru Okazaki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Functional Recovery ◽  
Capillary Density ◽  
Left Ventricular ◽  
Wild Type ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
And Function

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS−/−), endothelial NOS-knockout (eNOS−/−), and neuronal NOS-knockout (nNOS−/−) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS−/− mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH4) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH2), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH4-to-BH2 ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS−/− mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS−/−, and nNOS−/− but not iNOS−/− mice. Nω-nitro-l-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.

Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition

2005 ◽  
Vol 288 (1) ◽  
pp. H149-H158 ◽  
Author(s):  
John S. Ikonomidis ◽  
Jennifer W. Hendrick ◽  
Andrea M. Parkhurst ◽  
Amanda R. Herron ◽  
Patricia G. Escobar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Wild Type ◽  
End Diastolic Volume ◽  
Coronary Ligation ◽  
Lv Remodeling ◽  
And Function ◽  
Deficient Mice

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 mg·kg−1·day−1) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/MMPi ( n = 10), TIMP1-KO-MI/MMPi ( n = 10), WT-MI ( n = 22), and TIMP1-KO-MI ( n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT ( n = 20) and TIMP1-KO ( n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 ± 2 and 40 ± 2 μl, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 ± 2 vs. 61 ± 5 μl, P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 ± 2 and 36 ± 2 μl, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice ( P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically “rescued” by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI.

Abstract 99: Ac-SDKP Protects the Heart From Post-myocardial Infarction Remodeling and Dysfunction in Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hongmei Peng ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Xiangguo Dai ◽  
Edward Petersion ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Posterior Wall ◽  
Capillary Density ◽  
Left Ventricular ◽  
Posterior Wall Thickness ◽  
Lv Remodeling ◽  
Anti Inflammatory ◽  
And Function ◽  
Fractional Shortening

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) has anti-inflammatory, anti-fibrotic and pro-angiogenic effects. We previously observed that Ac-SDKP reduces incidence of cardiac rupture in mice with acute myocardial infarction (MI), which is associated with its anti-inflammatory and pro-angiogenic properties. We hypothesized that Ac-SDKP, via its anti-fibrotic and pro-angiogenic actions, ameliorates left ventricular (LV) dilatation and fibrosis, thus improving cardiac function post-MI. C57BL/6J mice were divided into three groups: 1) sham MI, 2) MI + vehicle (VEH), and 3) MI + Ac-SDKP. Ac-SDKP (1.6 mg/kg/day) was given immediately after MI induction ( i.p. via osmotic pump) for 5 weeks. Cardiac remodeling and function were assessed by echocardiography, and interstitial collagen fraction (ICF) and capillary density was determined histologically. We found that Ac-SDKP 1) reduced LV remodeling, evidenced by decreased LV chamber dimensions and areas, and reduced ICF and increased capillary density, with no changes in posterior wall thickness and LV weight (LVW), and 2) improved cardiac function, demonstrated by increased fractional shortening (FS) and ejection fraction (EF) (Table). We conclude that in murine models of MI, Ac-SDKP protects the heart from more severe remodeling and dysfunction, possibly via its anti-fibrotic and pro-angiogenic actions. Thus, the use of Ac-SDKP or its analogues could be a new and effective alternative in restoring cardiac function in patients after MI.

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.

Cardiac magnetic resonance T1 mapping allows for predicting adverse left ventricular remodeling post-reperfused st-elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Zhang ◽  
Y.K Guo ◽  
Z.G Yang ◽  
M.X Yang ◽  
K.Y Diao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T1 Mapping ◽  
Ventricular Remodeling ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Funding Source ◽  
Native T1 ◽  
End Diastolic Volume ◽  
Significant Difference ◽  
Lv Remodeling

Abstract Background Cardiac magnet resonance (CMR) T1 mapping allows the quantitative characterization of the severity of tissue injury and predict functional recovery in acute myocardial infarction (AMI). Purpose The study aimed to investigate whether native T1 and ECV of infarct myocardium are influenced by microvascular obstruction (MVO) and have predictive value for adverse left ventricular (LV) remodeling post-infarction. Method A cohort of 54 patients with successfully reperfused STEMI underwent CMR imaging at a 3T scanner in AMI and 3 months post-infarction. Native T1 data was acquired using a modified Look-Locker inversion recovery (MOLLI) sequence, and ECV maps were calculated using blood sampled hematocrit. Manual regions-of-interest were drawn within the infarct myocardium to measure native T1 and ECV (native T1infarct and ECVinfarct, respectively). MVO identified as a low-intensity area within the infarct zone on LGE was eliminated. Results MVO was present in 36 patients (66.67%) in AMI. ECVinfarct in patients with MVO was different from those without (58.66±8.71% vs. 49.64±8.82%, P=0.001), while no significant difference in T1infarct was observed between patients with and without MVO (1474.7±63.5ms vs. 1495.4±98.0ms, P=0.352). ECV correlated well with the change in end-diastolic volume (all patients: r=0.564, P&lt;0.001) and predicted LV remodeling in patients with and without MVO (rMVO absent = 0.626, P=0.005; rMVO present = 0.686, P&lt;0.001; all patients: r=0.622, P&lt;0.001); Native T1 was only associated with a 3-month change in LV end-diastolic volume (rMVO absent= 0.483, P=0.042) and predicted LV remodeling in patients without MVO (rMVO absent = 0.659, P=0.003). Furthermore, ECV had an association with LV remodeling (β=0.312, P=0.007) in multivariable logistic analysis. Conclusion Absolute native T1 in infarct myocardium might be affected by MVO but ECV isn't. ECV could predict LV remodeling in MI patients with and without MVO, while native T1 predict it in MI with MVO absent. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University

Sepiapterin prevents left ventricular hypertrophy and dilatory remodeling induced by pressure overload in rats

2015 ◽  
Vol 309 (10) ◽  
pp. H1782-H1791 ◽  
Author(s):  
Kei Yoshioka ◽  
Hajime Otani ◽  
Takayuki Shimazu ◽  
Masanori Fujita ◽  
Toshiji Iwasaka ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Salvage Pathway ◽  
Aortic Constriction ◽  
Beneficial Effects ◽  
Lv Remodeling

Uncoupling of nitric oxide (NO) synthase (NOS) has been implicated in left ventricular (LV) hypertrophy (LVH) and dilatory remodeling induced by pressure overload. We investigated whether administration of sepiapterin, a substrate of the salvage pathway of tetrahydrobiopterin synthesis, prevents LVH and dilatory LV remodeling by inhibiting NOS uncoupling and increasing bioavailable NO. Pressure overload was induced in rats by transverse aortic constriction (TAC). Concentric LVH developed during 8 wk after TAC, and dilatory LV remodeling and dysfunction developed between 8 and 16 wk after TAC associated with a decrease in capillary density. Oral administration of sepiapterin or the superoxide/peroxynitrite scavenger N-(2-mercaptopropionyl)-glycine for 8 wk after TAC inhibited oxidative stress, but only sepiapterin increased bioavailable NO and inhibited cardiomyocyte hypertrophy associated with a further increase in capillary density. When sepiapterin was administered between 8 and 16 wk after TAC, cardiomyocyte hypertrophy was regressed and capillary density was restored. This was associated with the inhibition of interstitial fibrosis and dilatory LV remodeling. N-nitro-l-arginine methyl ester abrogated all the beneficial effects of sepiapterin in rats with TAC. These results suggest that sepiapterin prevents concentric LVH and dilatory remodeling after TAC primarily by increasing the bioavailability of NO.

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling

Cardiology ◽  
2017 ◽  
Vol 138 (2) ◽  
pp. 91-96 ◽  
Author(s):  
Sam C. Latet ◽  
Paul L. Van Herck ◽  
Marc J. Claeys ◽  
Amaryllis H. Van Craenenbroeck ◽  
Steven E. Haine ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Healthy Subjects ◽  
Noncoding Rna ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Circulating Microrna ◽  
Second Phase ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
St Elevation

Background: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. Aims: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). Methods: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. Results: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). Conclusion: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.

Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction

2009 ◽  
Vol 296 (5) ◽  
pp. H1513-H1523 ◽  
Author(s):  
Monique C. de Waard ◽  
Jolanda van der Velden ◽  
Nicky M. Boontje ◽  
Dick H. W. Dekkers ◽  
Rien van Haperen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Training ◽  
Left Ventricular ◽  
Lv Function ◽  
Enos Expression ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Enos Uncoupling ◽  
Lv Remodeling ◽  
Exercise Induced

It has been reported that exercise after myocardial infarction (MI) attenuates left ventricular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Both exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development (Fmax). However, only exercise training restored myofilament Ca2+-sensitivity and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca2+ homeostasis, as myofilament Fmax actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and l-arginine prevented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament Fmax. In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after MI, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS “uncoupling.”

scholarly journals Clinical outcome and left ventricular remodeling in AMI patients with insufficient myocardial reperfusion after recanalization

2010 ◽  
Vol 33 (5) ◽  
pp. 304 ◽  
Author(s):  
Jun Jin ◽  
Hong Wang ◽  
Yao-Ming Song ◽  
Ai-Ming Li ◽  
Jun Qin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Functional Recovery ◽  
Left Ventricular ◽  
Myocardial Reperfusion ◽  
Timi Flow Grade ◽  
Timi Flow ◽  
Lv Remodeling ◽  
Group A ◽  
Grade 3 ◽  
Group B

Aim: Myocardial contrast echocardiography (MCE) is effective in predicting myocardial viability and functional recovery on a segmental level in patients with acute myocardial infarction (AMI). In this study, we investigated whether insufficient myocardial reperfusion plays an important role in left ventricular (LV) remodeling and functional recovery in patients with thrombolysis in myocardial infarction (TIMI) flow grade 3 and corrected TIMI frame count (CTFC) < 40 after recanalization of the infarct-related artery. Method: Patients underwent intracoronary injection of microbubbles for echocardiographic assessment of myocardial microvascular perfusion, wall motion score, LV volume and ejection function (EF) at baseline, 30 minutes, one month and six months after recanalization. The patients with MCESI < 1 were considered to have insufficient myocardial reperfusion (group A, n=11), while the patients with MCESI≥1 were considered to have sufficient myocardial reperfusion (group B, n=47) after AMI recanalization. Results: The wall motion score index (WMSI) and the left ventricular ejection fraction (LVEF) showed significant improvement at 1 month and 6 months in group B, but only at six months in group A. Left ventricular end-systolic and end-diastolic volumes (LVESV and LVEDV) were also significantly decreased at one and six months in group B. WMSI, LVESV, LVEDV and LVEF were significantly improved in group B in comparison with group A at one month and six months (P < 0.01). By six months, significant correlations were seen in all patients between MCESI and changes in LVESV, LVEDV and LVEF at 6 months. Similar correlations were observed between the myocardial regional blood flow (Q) and changes in LVESV , LVEDV and LVEF.. Conclusion: Insufficient myocardial reperfusion was a strong independent predictor of LV remodeling and functional recovery in AMI patients with TIMI flow grade 3 and CTFC < 40 after recanalization. MCE has important additional value for prognosis and risk assessment in patients with acute myocardial infarction following recanalization.

Abstract 1412: Critical Role Of Extracellular Sod For Protecting The Heart Against Myocardial Hypertrophy And Dysfunction After Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elza D Deel ◽  
Zhongbing LU ◽  
Xin Xu ◽  
Guangshuo Zhu ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Superoxide Anion ◽  
Left Ventricular ◽  
Wild Type ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Lv Remodeling ◽  
Anion Production ◽  
Lv Ejection Fraction

Extracellular SOD ( SOD3 ) contributes only a small fraction to total SOD activity in the normal heart, but is strategically located to scavenge free radicals in the extracellular compartment. SOD3 expression is decreased in the failing heart, but whether SOD3 can abrogate oxidative stress or modify left ventricular (LV) remodeling following myocardial infarction (MI) is unclear. To examine this question, we studied LV remodeling in SOD3 KO mice and wild type mice following MI. Under unstressed conditions, SOD3 KO had no effect on myocardial total SOD activity, SOD1 or SOD2 protein content, or myocardial nitrotyrosine or superoxide anion production, and caused no change in LV ejection fraction. However, 4 weeks or 8 weeks after MI, SOD3 KO mice developed more LV hypertrophy (8 weeks after MI, ventricular mass increased 1.64-fold in KO mice as compared to 1.35-fold in wild type mice, p<0.01) and had a greater reduction of LV ejection fraction (8 weeks after MI, LV ejection fraction was 35±2.4% in wild type mice as compared to 30±2.0% in KO mice, p<0.01). As compared with wild type mice, SOD3 KO mice had significantly greater increases of myocardial nitrotyrosine and superoxide anion production, a significantly greater decrease of ANP in the peri-infarct zone, and a significant more decrease of SERCA2a in both the peri-infarct and remote zones. In addition, MI caused greater activation of mitogen-activated protein kinase (MAPK) signaling pathways in SOD3 KO mice, as demonstrated by significantly greater increases of p-p38 Thr180/ Tyr182 , p-Erk Thr202/Tyr204 and p-JNK Thr183/Tyr185 in SOD3 KO mice 8 weeks after MI. The finding that SOD3 KO had no effect on myocardial total SOD activity, but significantly exacerbated MI induced LV remodeling implies that the specific extracellular location of SOD3 is more important than its contribution to overall SOD activity in protecting the heart against contractile dysfunction following myocardial infarct.

Abstract 1890: Depletion of Transplanted Pro-Angiogenic Cells by a Suicide Approach Discloses a Crucial Role of Sustained Incorporation for Cardiac Repair after Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Chang-hwan Yoon ◽  
Thomas Ziebart ◽  
Thomas Trepels ◽  
Astrid Wietelsbacher ◽  
Thomas Braun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Capillary Density ◽  
Left Ventricular ◽  
Functional Improvement ◽  
Left Ventricular Ejection ◽  
Specific Cell ◽  
Ventricular Ejection Fraction ◽  
Beneficial Effects ◽  
Active Promoter ◽  
Constitutively Active

Endothelial progenitor cells improve neovascularisation of ischemic tissue by a broad repertoire of potential mechanisms. While initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. The question remains to what extent a physical incorporation is contributing to the beneficial effects of cell therapy. Pro-angiogenic cells were cultivated from peripheral blood mononuclear cells under conditions favouring endothelial commitment (“early EPC”) and were transduced with a lentiviral vector encoding thymidine kinase (TK) under the control of constitutively active promoter. TK activates the pro-drug gancyclovir (GV) to induce toxicity in the target cell. Injection of cells in mice after acute myocardial infarction (MI) significantly improved left ventricular ejection fraction (EF) as assessed by MRI and echocardiography up to 4 weeks compared to control mice. However, depletion of the TK-expressing cells by GV treatment at 2 weeks after cell infusion was associated with deterioration of EF measured at 4 weeks (no cells:37 ± 5%;TK-cells:61 ± 5.6%,TK-cells + GV:43 ± 4.6%). Likewise, endsystolic volume was significantly reduced in mice injected with TK-cells but was increased by cell depletion with GV. Consistently, the increased capillary density in TK-cell-treated mice was significantly reduced by GV treatment (lectin + area: TK-cells: 11 ± 2.0, TK-cells+GV: 6.8 ± 2.5, p < 0.05). In order to examine the contribution of lineage-committed cells after MI, we selectively depleted KDR-positive cells by expressing TK under the control of the KDR-promoter. Injection of gancyclovir after 2 weeks in KDR-TK-cell treated mice also resulted in a deterioration of the EF measured at 4 weeks, however, the effect was less pronounced compared to the depletion of all cells by using the constitutively active promoter. Conclusion: Depletion of infused cells 2 weeks after MI induced a decline of EF and capillary density. These data document that infused cells are physically incorporated weeks after transplantation. The contribution of specific cell lineages to the maintenance of functional improvement warrants further investigations.

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