Frank Griscelli

Publications (13)62.91 Total impact

• Article: Malignant germ cell-like tumors, expressing Ki-1 antigen (CD30), are revealed during in vivo differentiation of partially reprogrammed human-induced pluripotent stem cells.

  Frank Griscelli, Olivier Féraud, Noufissa Oudrhiri, Emilie Gobbo, Ibrahim Casal, Jean-Claude Chomel, Ivan Biéche, Pierre Duvillard, Paule Opolon, Ali G Turhan, Annelise Bennaceur-Griscelli
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  ABSTRACT: Because many of the genes used to produce induced pluripotent stem cells (iPSCs) from somatic cells are either outright established oncogenes, such as c-myc and Klf4, or potentially related to tumorigenesis in various cancers, both the safety and the risks of tumorigenesis linked to iPSC generation require evaluation. In this work, we generated, by lentivirus-mediated gene transfer of Oct4, Sox2, Nanog, and Lin28, two types of iPSCs from human mesenchymal stem cells and human amniotic fluid-derived cells: fully reprogrammed iPSCs with silencing of the four transgenes and partially reprogrammed iPSCs that still express one or several transgenes. We assessed the behavior of these cells during both their differentiation and proliferation using in vivo teratoma assays in nonobese diabetic mice with severe combined immunodeficiency. In contrast to fully reprogrammed iPSCs, 43% of partially reprogrammed iPSC cases (6 of 14 teratomas) generated major dysplasia and malignant tumors, with yolk sac tumors and embryonal carcinomas positive for α-fetoprotein, cytokeratin AE1/AE3, and CD30. This correlated with the expression of one or several transgenes used for the reprogramming, down-regulation of CDK 1A mRNA (p21/CDKN1A), and up-regulation of antiapoptotic Bcl-2 mRNA. Therefore, the oncogenicity of therapeutically valuable patient-specific iPSC-derived cells should be scrupulously evaluated before they are used for any clinical applications.
  American Journal Of Pathology 03/2012; 180(5):2084-96. · 4.89 Impact Factor
• Source

  Available from: Ali G Turhan

  Article: Identification of spectral modifications occurring during reprogramming of somatic cells.

  Christophe Sandt, Olivier Féraud, Noufissa Oudrhiri, Marie Laure Bonnet, Marie Claude Meunier, Yannick Valogne, Angelina Bertrand, Martine Raphaël, Frank Griscelli, Ali G Turhan, Paul Dumas, Annelise Bennaceur-Griscelli
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  ABSTRACT: Recent technological advances in cell reprogramming by generation of induced pluripotent stem cells (iPSC) offer major perspectives in disease modelling and future hopes for providing novel stem cells sources in regenerative medicine. However, research on iPSC still requires refining the criteria of the pluripotency stage of these cells and exploration of their equivalent functionality to human embryonic stem cells (ESC). We report here on the use of infrared microspectroscopy to follow the spectral modification of somatic cells during the reprogramming process. We show that induced pluripotent stem cells (iPSC) adopt a chemical composition leading to a spectral signature indistinguishable from that of embryonic stem cells (ESC) and entirely different from that of the original somatic cells. Similarly, this technique allows a distinction to be made between partially and fully reprogrammed cells. We conclude that infrared microspectroscopy signature is a novel methodology to evaluate induced pluripotency and can be added to the tests currently used for this purpose.
  PLoS ONE 01/2012; 7(4):e30743. · 4.09 Impact Factor
• Article: Antitumorigenic effects of a mutant of the heparin affin regulatory peptide on the U87 MG glioblastoma cell line

  Célia Dos Santos, Racha Karaky, Dominique Renoir, Yamina Hamma-Kourbali, Patricia Albanese, Emilie Gobbo, Frank Griscelli, Paule Opolon, Sophie Dalle, Michel Perricaudet, José Courty, Jean Delbé
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  ABSTRACT: Glioblastoma is the most common primary brain tumor in human adults. Since existing treatments are not effective enough, novel therapeutic targets must be sought. The heparin-binding growth factor, heparin affin regulatory peptide (HARP), also known as pleiotrophin (PTN), could potentially represent such a target. We have previously shown that a mutant protein, HARPΔ111–136, which lacks HARP's C-terminal 26 amino acids, acts as a dominant negative HARP effector by heterodimerizing with the wild-type growth factor. The aim of our study was to evaluate the potential inhibitory activity of HARPΔ111–136 on the U87 MG human glioblastoma cell line. By overexpressing the truncated form of HARP in stably established clones of U87 MG cells, we observed an inhibition of proliferation under both anchorage-dependent and anchorage-independent conditions. We confirmed these results in an in vivo subcutaneous tumor xenograft model. In addition, we found that HARPΔ111–136 inhibited cell proliferation in a paracrine manner. Analysis of key cellular pathways revealed a decrease of cell adhesion in U87 MG cells that overexpressed the mutant protein, which could explain this inhibitory effect. A replication-defective adenovirus model that encoded HARPΔ111–136 supported a putative antiproliferative role for the truncated protein in vitro and in vivo. Interestingly, HARPΔ111–136 was also able to abolish angiogenic activity in HUVEC proliferation and in a Matrigel plug assay. These results demonstrate that considering its antiproliferative and angiostatic effects, HARPΔ111–136 could be of great interest when used in conjunction with standard treatments.
  International Journal of Cancer 12/2009; 127(5):1038 - 1051. · 5.44 Impact Factor
• Article: 16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development.

  Aurélie Ducès, Racha Karaky, Dominique Martel-Renoir, Lluis Mir, Yamina Hamma-Kourbali, Ivan Biéche, Paule Opolon, Jean Delbé, José Courty, Michel Perricaudet, Frank Griscelli
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  ABSTRACT: Pleiotrophin (PTN) is a 136-amino acid secreted heparin-binding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTNDelta111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTNDelta111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTNDelta111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1alpha mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTNDelta111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTNDelta111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer.
  Molecular Cancer Therapeutics 10/2008; 7(9):2817-27. · 5.23 Impact Factor
• Article: Amino-terminal fragment of urokinase inhibits tumor cell invasion in vitro and in vivo: respective contribution of the urokinase plasminogen activator receptor-dependent or -independent pathway.

  Hong Li, Claudine Soria, Frank Griscelli, Paule Opolon, Jeannette Soria, Patrice Yeh, Chantal Legrand, Jean Pierre Vannier, Dominique Belin, Michel Perricaudet, He Lu
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  ABSTRACT: The urokinase plasminogen activator (uPA) is implicated in both cancer cell invasion and angiogenesis. It can interact with a specific receptor (uPAR) via the epidermal growth factor (EGF)-like domain in the urokinase amino-terminal fragment (ATF) in a species-specific manner. Our previous studies showed that adenovirusmediated delivery of murine ATF (AdmATF) suppressed human tumor growth in mouse models, by inhibiting murine angiogenesis. However, we cannot exclude its putative inhibitory action on human cancer cell invasion through a uPAR-independent pathway. To further investigate the mechanisms of ATF, we constructed another adenovirus, AdhmATF, expressing humanized murine ATF (hmATF). hmATF binds to human uPAR but not to murine uPAR. We compared the antagonist effect of both AdmATF and AdhmATF on human and murine cancer cells. In vitro, the supernatant from AdhmATF-infected cells repressed 79% of membrane-associated uPA activity on human MDA-MB-231 cells, whereas that from AdmATF-infected cells repressed 35% of membrane-associated uPA activity. On murine LLC cells, the supernatant from AdhmATF-infected cells inhibited 29% of cell surface uPA activity, whereas that from AdmATF-infected cells inhibited 74% of cell surface uPA activity. Similar results were obtained in a cell invasion assay. In vivo, intratumoral injection of the adenoviruses into LLC tumors on day 24 postinjection induced lower but significant tumor growth suppression by AdhmATF (tumor volume was 1185 +/- 128 mm3), whereas suppression by AdmATF was greater (407 +/- 147 mm3). In the MDA-MB-231 tumor model, on day 52 postinjection, tumor size was 187 +/- 47 mm3 in the AdhmATF-treated group and 468 +/- 65 mm3 in the AdmATF-treated group. The LLC and MDA-MB- 231 cell lines transfected by mATF or hmATF genes showed growth inhibition In vivo equivalent to the results obtained by adenovirus treatment. These results demonstrate the strong anticancer activity of ATF even when its uPAR-binding affinity has been suppressed, and indicate that ATF exerts an antitumor effect via dual mechanisms: essentially through targeting the uPA-uPAR system via the EGF-like domain and partially through targeting a uPAR-independent interaction via the kringle domain.
  Human Gene Therapy 11/2005; 16(10):1157-67. · 4.22 Impact Factor
• Article: Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with alphavbeta3 and alphavbeta5 integrins.

  Claire Magnon, Ariane Galaup, Brian Mullan, Valérie Rouffiac, Céline Bouquet, Jean-Michel Bidart, Frank Griscelli, Paule Opolon, Michel Perricaudet
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  ABSTRACT: Canstatin, the noncollagenous domain of collagen type IV alpha-chains, belongs to a series of collagen-derived angiogenic inhibitors. We have elucidated the functional receptors and intracellular signaling induced by canstatin that explain its strong antitumor efficacy in vivo. For this purpose, we generated a canstatin-human serum albumin (CanHSA) fusion protein, employing the HSA moiety as an expression tag. We show that CanHSA triggers a crucial mitochondrial apoptotic mechanism through procaspase-9 cleavage in both endothelial and tumor cells, which is mediated through cross-talk between alphavbeta3- and alphavbeta5-integrin receptors. As a point of reference, we employed the first three kringle domains of angiostatin (K1-3), fused with HSA, which, in contrast to CanHSA, act only on endothelial cells through alphavbeta3-integrin receptor-mediated activation of caspase-8 alone, without ensuing mitochondrial damage. Taken together, these results provide insights into how canstatin might exert its strong anticancer effect.
  Cancer Research 06/2005; 65(10):4353-61. · 7.86 Impact Factor
• Article: High level of stabilized angiostatin mediated by adenovirus delivery does not impair the growth of human neuroblastoma xenografts.

  Jean-Marc Joseph, Cèline Bouquet, Paule Opolon, Jackie Morizet, Geneviève Aubert, Jochen Rössler, Nicole Gross, Frank Griscelli, Michel Perricaudet, Gilles Vassal
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  ABSTRACT: Human neuroblastoma (NB) is a highly heterogeneous childhood cancer secreting a high level of vascular endothelial growth factor (VEGF). Its vascularization has been clearly correlated with metastatic progression and poor outcome. Thus, molecules that target the vascular endothelium are regarded as new therapeutics of clinical interest. Angiostatin, an internal fragment of plasminogen containing the first four kringle structures, has been described as a powerful angiogenic inhibitor. We used a recombinant adenovirus encoding the human angiostatin kringle 1-3 directly fused to human serum albumin HSA (AdK3-HSA). Coupling to HSA has been previously shown to increase the in vivo half-life of this angiostatic factor, and to lead to tumor growth inhibition in the MDA-MB-231 carcinoma model. For the assessment of antiangiogenic gene therapy in the human NB IGR-N835 tumor model, 5 x 10(9) PFU of AdK3-HSA were intravenously injected in tumor-bearing athymic mice presenting either of the following experimental settings: early stage, established, and minimal residual tumors. No delay in tumor growth was observed in animals treated with AdK3-HSA as compared to those treated with the empty virus AdCO1. In early-stage tumors, kinetics of tumor occurrence and tumor growth were similar in AdK3-HSA- and AdCO1-treated animals. K3-HSA was found to be expressed at high levels (the mean value for the three experiments being 19.4+/-15.9 microg/ml) in the circulation of all animals up to 21-35 days after virus injection. In addition, IGR-N835 tumors were found to be highly vascularized and to release high amounts of angiogenic factors, in particular VEGF (665+/-370 pg/mg total protein). Thus, in spite of high circulating levels, K3-HSA may be unable to displace the NB proangiogenic switch. In this regard, a more promising target to inhibit NB angiogenesis seems to be the VEGF/VEGFR system.
  Cancer Gene Therapy 12/2003; 10(11):859-66. · 2.80 Impact Factor
• Article: Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice.

  Marie-Aude Pascaud, Frank Griscelli, William Raoul, Elisabeth Marcos, Paule Opolon, Bernadette Raffestin, Michael Perricaudet, Serge Adnot, Saadia Eddahibi
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  ABSTRACT: Exposure to hypoxia leads to the development of pulmonary hypertension (PH) as a consequence of pulmonary smooth muscle hyperplasia. Hypoxia concomitantly stimulates lung expression of angiogenic factors. To investigate the role of angiogenesis processes in development of hypoxic PH, we examined the effects of lung overexpression of angiostatin, an angiogenesis inhibitor, on development of hypoxic PH and lung endothelial cell (EC) density. Angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molcule driven by the cytomegalovirus promoter (Ad.K3). Comparison was made with a control vector containing no gene in the expression cassette (Ad.CO1). Treatment with Ad.K3 (300 plaque-forming units [pfu]/cell) inhibited cultured human pulmonary artery EC migration by 100% and proliferation by 50%, but was without effects on human pulmonary artery smooth muscle cells. After intratracheal administration of Ad.K3 (109 pfu) to mice, angiostatin protein became detectable in bronchoalveolar lavage fluid. Mice pretreated with Ad.K3 1 d before a 2-wk exposure to hypoxia (10% O2) showed more severe pulmonary hypertension than Ad.CO1-pretreated controls, as assessed by higher right ventricular systolic pressure (36.5 +/- 2.4 versus 30.2 +/- 1.4, respectively), aggravation of right ventricular hypertrophy (P < 0.05), and muscularization of distal vessels (P < 0.01). Lung factor VIII, CD31 immunostaining, as well as eNOS expression were significantly increased after exposure to hypoxia in Ad.CO1-pretreated controls, but decreased in both normoxic and hypoxic animals after treatment with Ad.K3. The results show that inhibition of hypoxia-induced stimulation of lung angiogenic processes aggravates development of hypoxic PH. This suggests that endogenous lung angiogenesis counteracts development of hypoxic PH.
  American Journal of Respiratory Cell and Molecular Biology 10/2003; 29(4):449-57. · 5.13 Impact Factor
• Article: Endostatin exhibits a direct antitumor effect in addition to its antiangiogenic activity in colon cancer cells.

  Fatima Dkhissi, He Lu, Claudine Soria, Paule Opolon, Frank Griscelli, Hanfeng Liu, Patricia Khattar, Zohar Mishal, Michel Perricaudet, Hong Li
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  ABSTRACT: Endostatin has been considered a highly specific inhibitor of endothelial cell proliferation and/or migration. To explore the use of endostatin in antiangiogenic gene therapy, we generated a recombinant adenovirus, AdEndo, carrying the gene for mouse endostatin. Injection of 10(9) PFU of AdEndo resulted in a low but significant suppression (25%) of preestablished tumor growth in murine models involving murine Lewis lung carcinoma (LLC) and human breast cancer MDA-MB-231 tumors. Greater anticancer activity was observed when the same dose of AdEndo was injected into two other preestablished murine models involving C51 murine colon cancer and HT29 human colon cancer (55 and 47% tumor growth reduction, respectively). In vitro, endostatin derived from AdEndo-infected MRC-5 fibroblasts inhibited the growth of C51 and HT29 cell lines (72 and 61%, respectively). The extent of this inhibition was comparable to that observed in endothelial cells: 75% for microcapillary endothelial cell line HMEC-1, 52% for human dermal microvascular endothelial cells, 46% for human umbilical vein endothelial cells, and 67% for calf pulmonary arterial endothelial cells. Both endothelial and colon cancer cells showed a clear increase in cell apoptosis (4- to 5-fold for endothelial cells and 5- to 10-fold for colon cancer cells) and an accumulation in the G(1) phase of the cell cycle. This antiproliferative activity was not observed in other tumor cell lines: LLC, MDA-MB-231, murine colon adenocarcinoma MC38, human prostate cancer cell line DU145, and human breast cancer cell line CAL51. Taken together, these results provide evidence that, in addition to its antiangiogenic activity, endostatin exerts a direct anticancer action that appears to be restricted to some tumor cell lines. Thus, endostatin could be used in some colon cancer treatments and its clinical efficacy would depend on the response of tumor cells themselves.
  Human Gene Therapy 08/2003; 14(10):997-1008. · 4.22 Impact Factor
• Article: Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model.

  Ariane Galaup, Paule Opolon, Céline Bouquet, Hong Li, David Opolon, Marie-Christine Bissery, Thomas Tursz, Michel Perricaudet, Frank Griscelli
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  ABSTRACT: The anti-tumor effects of adenovirus-delivered angiostatin (AdK3) in association with docetaxel (Taxotere) have been evaluated in a human-origin prostate tumor model. In vitro, human endothelial cells were 50- to 100-fold more sensitive to docetaxel than prostate cell lines (PC3, LNCaP, and DU145), and the combination regimen of docetaxel and AdK3 was significantly more cytotoxic for endothelial cells than either treatment alone. PC3 cells, which display the highest sensitivity to docetaxel, were then grafted onto athymic mice for an evaluation of the combined regimen as a therapy. The combination of a single intratumoral injection of AdK3 (2 x 10(9) pfu) and a single intravenous injection of docetaxel (15 mg/kg) was compared with the injection of AdK3 alone on preestablished mice bearing PC3-derived tumors with a mean tumor volume of 60 +/- 11 or 205 +/- 46 mm3. Significant antitumoral effects were observed only in mice receiving the combined treatment. We showed that all PC3 tumors regressed in the AdK3-docetaxel combination group and that 40 to 83% totally regressed. In all cases, this regimen was tightly correlated with a marked decrease in intratumoral vascularization. Our experimental data show that attacking both endothelial and tumoral compartments is an efficient and logical strategy, making this bitherapy approach clinically promising.
  Molecular Therapy 07/2003; 7(6):731-40. · 6.87 Impact Factor
• Article: Adenovirus-mediated gene transfer to the transplanted piglet heart after intracoronary injection.

  Frank Griscelli, Emre Belli, Paule Opolon, Karine Musset, Elisabeth Connault, Michel Perricaudet, Alain Serraf, Guy-Michel Mazmanian, Thierry Ragot
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  ABSTRACT: The advent of cardiac gene therapy in clinical practice requires a more efficient and safer myocardial gene delivery in large animals. A new approach to adenovirus-mediated intracoronary gene transfer in the piglet, using a heterotopic heart transplantation model, was designed to maximize the duration of contact between the vector and the heart in noncoronary flow conditions. Recombinant adenoviruses harboring a nucleus-localized beta-galactosidase gene under the control of a viral promoter were injected into the coronary vessels of the harvested hearts at a dose ranging from 10(10) to 2 x 10(11) pfu. The graft was maintained for 75 min in saline solution and then implanted in the abdomen of recipients. Gene transfer to allografts was evaluated 4 days after grafting by immunohistochemical and enzymatic analysis of beta-galactosidase expression. Transgene expression was detected in all cardiac areas and up to 64, 44, 32, and 15% of positive nuclei were estimated in the left ventricle wall in four animals out of eleven. In the remaining animals, transgene expression was focally distributed, mainly in the left ventricle wall. PCR analysis revealed the presence of adenoviral sequences, albeit minimal, in exposed organs such as the liver and lung. This procedure demonstrated that direct intracoronary gene transfer can be achieved using an ex vivo gene transfer strategy.
  The Journal of Gene Medicine 03/2003; 5(2):109-19. · 2.48 Impact Factor
• Source

  Available from: pnas.org

  Article: Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model

  Frank Griscelli, Hong Li, Chiat Cheong, Paule Opolon, Annelise Bennaceur-Griscelli, Gilles Vassal, Jeannette Soria, Claudine Soria, He Lu, Michel Perricaudet, Patrice Yeh
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  ABSTRACT: The objective of the present study was to evaluate the antitumor effect of a defective adenovirus expressing a secretable angiostatin-like molecule (AdK3) in combination with radiotherapy in rat C6 gliomas s.c. preestablished into athymic mice. In vitro, the combination regimen was significantly (P < 0.001) more cytotoxic for human microcapillary endothelial cells than either treatment alone, whereas survival of C6 glioma cells was not affected in the conditions used. Radiotherapy and AdK3 gene delivery was then studied on well established C6 xenografts (165 ± 70 mm3). In these tumors, AdK3 intratumoral injections had only a marginal effect. Interestingly, when experimental radiotherapy was added, significantly higher (P < 0.005), and possibly synergistic, antitumoral effects were observed that tightly correlated a marked decrease of intratumoral vascularization. The combination of radiotherapy and AdK3 intratumoral injections also revealed a significant (P < 0.05) inhibition of tumor growth as compared with either treatment alone for larger tumors (467 ± 120 mm3). Altogether, these data emphasize the potential of combining a destructive strategy directed against the tumor cells with an anti-angiogenic approach to fight cancer.
  Proceedings of the National Academy of Sciences 06/2000; 97(12):6698-6703. · 9.68 Impact Factor
• Article: Adenoviral SERCA1a gene transfer to adult rat ventricular myocytes induces physiological changes in calcium handling

  Nathalie Chossat, Frank Griscelli, Philippe Jourdon, Damien Logeart, Thierry Ragot, Michèle Heimburger, Michel Perricaudet, Anne-Marie Lompré, Stéphane Hatem, Jean-Jacques Mercadier
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  ABSTRACT: Objective: We examined the functional consequences of expressing adult rabbit fast skeletal sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA1a) in isolated adult rat ventricular myocytes. Methods: Myocytes were infected with a recombinant adenovirus harboring SERCA1a. Then 2 days after myocyte infection, protein expression was estimated using Western blot and SDS–PAGE analysis. We also measured the ATP-dependent oxalate-facilitated Ca2+ uptake of myocyte homogenates and monitored Ca2+ transient in myocytes loaded with the Ca2+ dye, indo-1. Results: SERCA1a gene expression resulted in a 36% increase in the total SERCA protein level in infected myocytes compared to controls ( P <0.01), while SERCA2 and phospholamban levels did not change. This increase was associated with a 42% rise in SR Ca2+ uptake ( P <0.01), while (the time constant of Ca2+ transient decay), and the time to peak fell by 32% ( P <0.01) and 38% ( P <0.001), respectively. Increasing the frequency of stimulation from 0.2 to 2 Hz decreased in both cell types ( P <0.01). However, the decrease was much smaller in infected ( P <0.01) than in uninfected cells ( P <0.001). Isoproterenol (1 µM) further decreased in infected myocytes by 23% ( P <0.05). In these cells, the diastolic [Ca2+]<SUB>i</SUB> decreased by 50% ( P <0.05) while the systolic [Ca2+]<SUB>i</SUB> increased by 19% ( P <0.05). No difference was found in the speed of SR Ca2+ reloading after caffeine washout between the two cell types. Conclusion: Adenovirus-mediated SERCA1a gene transfer to adult rat ventricular myocytes enhances SR Ca2+ handling to a degree similar to that observed following physiological stimulation.