Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.120.046372
ISSN1524-4539
AutoresTian Liang, Feng Gao, Jun Jiang, Yao Wei Lu, Feng Zhang, Yingchao Wang, Ning Liu, Xuyang Fu, Xiaoxuan Dong, Jianqiu Pei, Douglas B. Cowan, Xinyang Hu, Jianan Wang, Da‐Zhi Wang, Jinghai Chen,
Tópico(s)Congenital heart defects research
ResumoHomeCirculationVol. 142, No. 22Loss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBLoss of Phosphatase and Tensin Homolog Promotes Cardiomyocyte Proliferation and Cardiac Repair After Myocardial Infarction Tian Liang, MS Feng Gao, PhD Jun Jiang, MD, PhD Yao Wei Lu, PhD Feng Zhang, BS Yingchao Wang, MS Ning Liu, MS Xuyang Fu, BS Xiaoxuan Dong, BS Jianqiu Pei, PhD Douglas B. Cowan, PhD Xinyang Hu, MD, PhD Jian'an Wang, MD, PhD Da-Zhi Wang, PhD Jinghai ChenPhD Tian LiangTian Liang Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Feng GaoFeng Gao Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Jun JiangJun Jiang Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. , Yao Wei LuYao Wei Lu https://orcid.org/0000-0001-6200-2974 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (Y.W.L., D.B.C., D-Z.W.). , Feng ZhangFeng Zhang Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Yingchao WangYingchao Wang Zhejiang University School of Medicine, and Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University (Y.W.), Hangzhou, China. , Ning LiuNing Liu Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Xuyang FuXuyang Fu Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Xiaoxuan DongXiaoxuan Dong https://orcid.org/0000-0002-3712-3720 Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. , Jianqiu PeiJianqiu Pei State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (J.P.). , Douglas B. CowanDouglas B. Cowan Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (Y.W.L., D.B.C., D-Z.W.). , Xinyang HuXinyang Hu Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. , Jian'an WangJian'an Wang Jian'an Wang, MD, PhD, Department of Cardiology, Provincial Key Laboratory of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jie-Fang Rd, Hangzhou, 310009, China. Email E-mail Address: [email protected] Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. , Da-Zhi WangDa-Zhi Wang Da-Zhi Wang, PhD, Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Enders Building, Room 1260, 320 Longwood Ave, Boston, MA 02115; Email E-mail Address: [email protected] https://orcid.org/0000-0003-1774-6549 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (Y.W.L., D.B.C., D-Z.W.). Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D-Z-W.). , Jinghai ChenJinghai Chen Jinghai Chen, PhD, Institute of Translational Medicine, Department of Cardiology of Second Affiliation Hospital, Zhejiang University School of Medicine, 268 Kai-Xuan Rd, North Central Building, Hangzhou, 310029, China; Email E-mail Address: [email protected] https://orcid.org/0000-0002-5401-047X Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital (T.L., F.G., J.J., F.Z., N.L., X.F., X.D., X.H., J.W., J.C.), Hangzhou, China. Institute of Translational Medicine (T.L., F.G., F.Z., N.L., X.F., X.D., J.C.), Hangzhou, China. Originally published30 Nov 2020https://doi.org/10.1161/CIRCULATIONAHA.120.046372Circulation. 2020;142:2196–2199The loss of cardiomyocytes after myocardial infarction (MI) in adult mammals leads to heart failure. We previously reported a regenerative role for the miR-17-92 cluster1 in post-MI cardiac repair by repressing phosphatase and tensin homolog (PTEN).2 Despite favorable effects of PTEN inactivation in heart disease and the suggestion that it is involved in hypertrophy,3,4 whether the loss of PTEN directly promotes cardiomyocyte proliferation to enhance myocardial repair in response to MI remains unknown.We generated cardiac-specific Pten knockout mice with a tamoxifen-inducible Cre-LoxP system and confirmed no significant differences in cardiac function or morphology between Pten conditional knock-out (cKO) mice (Ptenflox/flox; α-myosin heavy chain [α-MHC]-MerCreMer) and control (Ptenflox/flox) mice (Figure [A]), which is consistent with previous reports.4 Although control mice exhibited heart failure at 2, 3, 4, 5, and 12 weeks after MI, cardiac function was preserved in Pten cKO mice (Figure [B]). Histological analyses revealed substantial reductions in infarct sizes of Pten cKO hearts at 15 weeks post-MI (Figure [C]). Cardiomyocyte size was markedly decreased in Pten cKO hearts at 12 weeks post-MI compared with the control group (Figure [D]).Download figureDownload PowerPointFigure. Loss of PTEN promotes cardiac regeneration and protects the heart from myocardial infarction.A, A schematic diagram of the research design and experimental procedures. Four-week-old Ptenfl/fl; α-MHC-MerCreMer (Pten cKO) mice, and Ptenfl/fl (control) mice were intraperitoneally injected with tamoxifen (75 mg/kg body weight). Four weeks later, these mice were subjected to myocardial infarction (MI) and assessed for cardiac function by echocardiography at the indicated time points before harvesting samples for analysis. B, Echocardiography of the Pten cKO group and control group at 2 to 5 weeks and 12 weeks post-MI (n=7–11 mice per group). Each data point represents an individual mouse. Data are represented as the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. C, Left, Representative images of serial transverse sections from the control and Pten cKO groups at 15 weeks after MI. Sirius red/fast green collagen staining marks the myocardium (green) and scar (red; scale bar, 2 mm). Right, Quantification of the scar size (n=5 hearts for control group; n=6 hearts for Pten cKO group). Each data point represents an individual mouse with analysis of 4 sections below the ligation for each heart. Infarct size (%) was calculated according to the formula: (length of coronal infarct perimeter [epicardial+endocardial]/total left ventricle coronal perimeter [epicardial+endocardial])×100. Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01,***P<0.001). Values of P<0.05 were considered statistically significant. D, Left, Immunofluorescence staining of WGA in cardiomyocytes of the papillary muscles in transverse sections from post-MI 12-week mouse hearts from control and Pten cKO mice. WGA marks cell membranes (white) for detecting cardiomyocyte size (scale bar, 50 μm). Right, Quantification of cardiomyocyte size (n=3 hearts for each group, each data point represents an individual mouse, enumerating 250–300 cells per heart). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. E, Left, Immunofluorescence staining of EdU incorporation in the MI border region in transverse sections from post-MI 15-week mouse hearts from control and Pten cKO mice. EdU labels proliferating cells (green), cTNT marks cardiomyocytes (red), WGA marks cell membranes (white), and DAPI labels nuclei (blue). Arrowheads point to EdU-positive signal in cardiomyocytes, asterisks mark EdU-positive signal in noncardiomyocytes (scale bars, 50 μm). Right, Quantification of the percentage of EdU-positive cardiomyocytes (n=3 hearts for each group, enumerating 2×103 to 3×103 myocytes per section; 2 sections from the border zone per heart, and each data point represents an individual mouse). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. F, Left, Immunofluorescence staining of pH3 in the border zone of 7-day post-MI mouse hearts from control and Pten cKO mice (PH3 [green]; cTNT [red]; WGA [white]; DAPI [blue]). Arrowheads point to pH3-positive signal in cardiomyocytes, asterisks mark pH3-positive signal in noncardiomyocytes (scale bars, 50 μm). Right, Quantification of pH3-positive cardiomyocytes (n=4 hearts for control group, n=6 hearts for Pten cKO group, enumerating 2×103 to 3×103 myocytes per section, 3–4 sections from the border zone in each heart). Each data point represents an individual mouse. Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. G, Left, Immunofluorescence staining of Aurora B kinase in the border zone using transverse sections from 7-day post-MI mouse hearts from control and Pten cKO mice. Aurora B (green); cTNT (red); WGA (white); and DAPI (blue). Arrowhead points to Aurora B kinase–positive signal in CMs, which is enlarged in the boxed area. Representative Z-stack 3D confocal microscopy showing a cytokinetic cardiomyocyte in a Pten cKO heart section (scale bars, 50 μm). Right, Quantification of Aurora B kinase–positive CMs (n=4 hearts for control group, n=6 hearts for Pten cKO group, enumerating 2×103 to 3×103 myocytes per section, 3–4 sections from the border zone of each heart). Each data point represents an individual mouse. Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. H, Lineage-tracing strategy and experimental design for assessing adult CM proliferation in the Pten genetic-deletion in vivo model. Ptenfl/fl; α-MHC-MerCreMer (Pten cKO) and α-MHC-MerCreMer (control) mice were bred with R26R-Confetti Cre-reporter mice. When treated with a low dose of tamoxifen, the expression of α-MHC led to Cre–loxP recombination and random labeling of CMs with a single color. I, Quantification of the clusters of 2 or more RFP+ CM clones in control and Pten cKO mouse hearts (scale bars, 50 μm; n=3 hearts per group). Quantification showing the ratio of the cells in clusters of two or more RFP+ cardiomyocytes/total RFP+ cardiomyocytes in Pten cKO and control groups (each data point represents an individual mouse, counting 3 sections per heart, enumerating 300±100 colored cells per section). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. J, Quantification of the clusters of 2 or more nGFP CMs in control and Pten cKO mouse hearts (scale bars, 50 μm; n=3 hearts per group). Quantification showing the ratio of cells in clusters of 2 or more nGFP+ CMs/total nGFP+ cardiomyocytes in Pten cKO and control groups (each data point represents an individual mouse, counting 3 sections per heart, enumerating 300±100 colored cells per section). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. K, Left, RNA-sequencing analysis of gene expression and enrichment differences between Pten cKO and control mouse hearts 7 days after MI. Right, Representative enrichment plots for perturbed extracellular matrix receptor interaction and cardiac muscle contraction (KEGG; n=4 hearts per group). L, Enrichment network map for perturbed GO biological processes gene sets in Pten-cKO-MI vs control-MI samples. Key clusters of the GO network were annotated in purple circles. The color of the circle denotes the direction of enrichment and the size of the circle denotes the size of the respective gene set. M, Quantitative real-time polymerase chain reaction to verify gene expression from the ECM- and contraction-associated, as well as cardiac disease–associated, genes (n=3 heart per group, each data point represents an individual mouse). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05). Values of P<0.05 were considered statistically significant. N, Left, Eight-week-old C57 mice were injected with the PTEN inhibitor VO-OHpic (10 μg/kg body weight) or DMSO (control). Cardiomyocytes were isolated and cultured in hypoxia (5% O2) and quantitative real-time polymerase chain reaction was used to detect the expression of cell cycle genes (n=4 hearts in DMSO group, n=5 hearts in VO-OHpic group; each data point represents an individual mouse). Right, Quantitative real-time polymerase chain reaction detection of the expression of cell cycle genes in neonatal rat cardiomyocytes cultured in hypoxia (0.1% O2; n=4 wells in siRNA-control group, n=3 wells in siRNA-Pten group). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). Values of P<0.05 were considered statistically significant. O, Schematic diagram of the therapeutic experimental design. Eight-week-old C57BL6J mice were subjected to surgically-induced MI and then intraperitoneally injected with DMSO (control) or PTEN inhibitor VO-Ohpic (10 μg/kg body weight) 6 hours after surgery. Cardiac function was assessed by echocardiography at the indicated times before harvesting heart samples for analysis. P, Echocardiography of mice treat with DMSO or VO-Ohpic at 2, 5, and 10 weeks post-MI (n=4–10 mice per group, each data point represents an individual mouse). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. Q, Left, Representative images of serial transverse sections from the control and VO-OHpic group at 12 weeks after MI. Sirius red/fast green collagen staining of myocardium (green) and scar (red; scale bar, 2 mm). Right, Quantification of the scar size (n=4 mice for each group; each data point represents an individual mouse, summarizing analysis of 5 sections for each sample). Infarct size was calculated according to the formula: (length of coronal infarct perimeter [epicardial+endocardial]/total left ventricle coronal perimeter [epicardial+endocardial])×100. Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05). Values of P<0.05 were considered statistically significant. R, The lineage-tracing strategy and experimental design for assessing adult CM proliferation in the PTEN-pharmacological inhibition in vivo model. α-MHC MerCreMer;R26R-Confetti mice were used to assess CM proliferation after tamoxifen activation of Cre-loxP recombination in the DMSO or VO-OHpic group post-MI. S, Quantification of the clusters of 2 or more RFP+ cardiomyocytes in DMSO and VO-OHpic–treated hearts (scale bars, 50 μm; n=3 mice per group). Quantification showing the ratio of the cells in clusters of 2 or more RFP+ cardiomyocytes / total RFP+ CMs in DMSO and VO-OHpic group (each data point represents an individual mouse, counting 3 sections per heart; 300±100 colored cells per section). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. T, Quantification of the clusters of 2 or more nuclear GFP+ (nGFP) cardiomyocytes in DMSO and VO-OHpic treated hearts (scale bars, 50 μm; n=3 mice per group). Quantification showing the ratio of the cells in clusters of 2 or more nGFP+ cardiomyocytes/total nGFP+ cardiomyocytes in DMSO and VO-OHpic groups (each data point represents an individual mouse, counting 3 sections per heart, 300±100 colored cells per section). Data represent the mean±SEM. Statistical analysis was performed using an unpaired, 2-tailed Student t test between 2 independent groups (*P<0.05, **P<0.01). Values of P<0.05 were considered statistically significant. cKO indicates conditional knockout; CM, cardiomyocyte; cTNT, cardiac troponin T; DAPI, 4′,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide; ECM, extracellular matrix; EdU, 5-ethynyl-2´-deoxyuridine; FS, fractional shortening (%); GO, gene ontology; KO, knockout; LVID;s, left ventricular internal dimension at end-systole; α-MHC, myosin heavy chain; MI, myocardial infarction; nGFP, nuclear GFP+; PTEN, phosphatase and tensin homolog; PH3, phospho-histone H3; KEGG, Kyoto Encyclopedia of Genes and Genomes; RFP, red fluorescent protein; siRNA, small interfering ribonucleic acid; and WGA, wheat germ agglutin.We detected a substantial increase in 5-ethynyl-2´-deoxyuridine (EdU) incorporation in adult cardiomyocytes from Pten cKO hearts (Figure [E]). This observation was supported by increased staining of the mitosis marker phospho-histone H3 (Figure [F]), as well as that of the cytokinesis marker Aurora B kinase, in adult cardiomyocytes of Pten cKO mice after MI (Figure [G]).To provide independent evidence that loss of Pten stimulated cardiomyocyte proliferation after MI, we used a lineage tracing strategy using a R26R-Confetti Cre-reporter system with a loxP-flanked multicolor fluorescent protein.5 We bred Ptenfl/fl; α-MHC-MerCreMer (Pten cKO) mice and α-MHC-MerCreMer (control) mice with R26R-Confetti Cre-reporter mice and used low-dose tamoxifen to induce Cre recombination to ensure Pten-deleted cardiomyocyte labeling with a single color. Four weeks later, we induced MI and assessed the amount of adjacent daughter cardiomyocytes that were the same color (Figure [H]). Quantification revealed that the clusters of 2 or more RFP+ (Figure [I]) and nuclear GFP+ (Figure [J]) cardiomyocytes were more frequently observed in Pten cKO hearts compared with control hearts. Together, these results demonstrate that the loss of Pten induces adult cardiomyocyte proliferation after MI.To gain a greater understanding of the effect of Pten deficiency on heart protection and regeneration after MI, we performed unbiased genome-wide transcriptional profiling; 1734 genes and 197 genes were down- and upregulated in the Pten cKO group, respectively, compared with the control group (q 0.5 log2 scale). Gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes pathway database revealed that downregulated genes were enriched for functional terms associated with the extracellular matrix and cell adhesion, whereas upregulated genes were associated with cardiac muscle contraction and metabolism (Figure [K]). In addition, the enrichment network for perturbed gene ontology biological process gene sets showed the key clusters annotated with extracellular matrix and inflammatory responses in the control group, and with cardiac muscle contraction, energy metabolism, and mitochondrial processes in the Pten cKO group after MI (Figure [L]). Subsequent quantitative real-time polymerase chain reaction verified this differential expression (Figure [M]). We found increased expression of cell cycle genes in isolated adult and neonatal cardiomyocytes with PTEN depletion on hypoxia treatment (Figure [N]). Collectively, these findings demonstrate that loss of PTEN protects the heart after MI injury by attenuating the inflammatory response and fibrotic remodeling in addition to enhancing contraction.To determine whether PTEN could be a potential therapeutic target, we treated mice with the PTEN inhibitor VO-OHpic after MI. Eight-week-old C57BL/6J mice were intraperitoneally injected with a low dose of VO-OHpic or dimethyl sulfoxide 6 hours after inducing MI (Figure [O]). PTEN inactivation by VO-OHpic significantly improved cardiac function (Figure [P]) and reduced scar formation (Figure [Q]). Overall, our data show that PTEN inhibition could be an effective therapeutic approach for treating infarcted hearts.Finally, using the R26R-Confetti Cre-reporter lineage tracing system (Figure [R]), we demonstrated that PTEN inhibition by VO-OHpic stimulated cardiomyocyte proliferation in MI-injured adult mouse hearts (Figure [S] and [T]). Together, our studies have uncovered an important and previously unrecognized role for PTEN inhibition in cardiac regeneration and repair, which may represent a therapeutic approach to protect the heart from ischemic injury and heart failure.All animals in this study conformed to the Public Health Service Guide for Care and Use of Laboratory Animals and was approved by the Institutional Animal Care and Use Committee of Zhejiang University.AcknowledgmentsThe authors thank the Core Facilities of Institute of Translational Medicine, Zhejiang University School of Medicine and the Laboratory Animal Center of Zhejiang University. We also thank Ms. Chao Bi, Ms. Xiaoli Hong and Ms. Chen Yang for help in histology and confocal microscopy.Sources of FundingThis work was supported by the National Key Research and Development Program of China (2017YFA0103700), the National Natural Science Foundation of China (Nos. 81470382, 81670257, 81970227 to J. Chen and No 82000244 to F. Gao), and the Zhejiang Provincial National Science Foundation project (LZ20H020001 to J. Chen) and the Postdoctoral Science Foundation of China (2020M671751 to F. Gao). Work from the Wang laboratory was supported by a grant from the National Institutes of Health (HL125925).DisclosuresNone.Footnotes*T. Liang and Drs Gao and Jiang contributed equally.https://www.ahajournals.org/journal/circData sharing: The data that support the findings of this study and research materials, as well as experimental procedures and protocols, are available from the corresponding author upon reasonable request by email.Jinghai Chen, PhD, Institute of Translational Medicine, Department of Cardiology of Second Affiliation Hospital, Zhejiang University School of Medicine, 268 Kai-Xuan Rd, North Central Building, Hangzhou, 310029, China; Email [email protected]edu.cnDa-Zhi Wang, PhD, Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Enders Building, Room 1260, 320 Longwood Ave, Boston, MA 02115; Email Da-Zhi.[email protected]harvard.eduJian'an Wang, MD, PhD, Department of Cardiology, Provincial Key Laboratory of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jie-Fang Rd, Hangzhou, 310009, China. Email [email protected]edu.cnReferences1. Chen J, Huang ZP, Seok HY, Ding J, Kataoka M, Zhang Z, Hu X, Wang G, Lin Z, Wang S, et al.. mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts.Circ Res. 2013; 112:1557–1566. doi: 10.1161/CIRCRESAHA.112.300658LinkGoogle Scholar2. Gao F, Kataoka M, Liu N, Liang T, Huang ZP, Gu F, Ding J, Liu J, Zhang F, Ma Q, et al.. Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction.Nat Commun. 2019; 10:1802. doi: 10.1038/s41467-019-09530-1CrossrefMedlineGoogle Scholar3. Oudit GY, Kassiri Z, Zhou J, Liu QC, Liu PP, Backx PH, Dawood F, Crackower MA, Scholey JW, Penninger JM. Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress.Cardiovasc Res. 2008; 78:505–514. doi: 10.1093/cvr/cvn041CrossrefMedlineGoogle Scholar4. Ruan H, Li J, Ren S, Gao J, Li G, Kim R, Wu H, Wang Y. 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