Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure

Salama, Abou Bakr M.; Gebreil, Ahmad; Mohamed, Tamer; Abouleisa, Riham

doi:10.3390/ijms22147720

Cited by 12 publications

(8 citation statements)

References 134 publications

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“…Many studies have explored novel therapeutics to promote cardiac regeneration to replenish cardiomyocyte numbers. 21,52,53 One study tested the novel concept that recapitulating the embryonic hypoxic environment, where low oxygen levels in the fetus supports the embryo development and cardiac growth, could reawaken adult myocyte proliferative properties. 23 In that study adult male mice were subjected to hypoxia (7% oxygen) and the results suggested an induction of large amounts of cardiomyocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Johnson

Yang

Bian

et al. 2023

Circulation Research

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BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

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Section: Discussionmentioning

confidence: 99%

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Johnson

Yang

Bian

et al. 2023

Circulation Research

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“…We and others previously showed that cardiomyocyte cell cycle induction after MI leads to a significant functional improvement in the heart (Abouleisa et al, 2022;Mohamed et al, 2018;Salama et al, 2022;Salama et al, 2021;Shapiro et al, 2014). In addition, our previous studies showed that 4F is an effective tool for inducing cell cycle and complete cytokinesis, which results in improved cardiac function after MI (Abouleisa et al, 2022;Mohamed et al, 2018).…”

Section: Discussionmentioning

confidence: 86%

“…To identify the target protein for the NDPPC that mediates cardiomyocyte proliferation, Autodock tool and Autodock vina software were used. First, we screened the 2D and 3D structures of NDPPC against the most prominent human cell cycle gene activators and inhibitors (Salama et al, 2021). The screening revealed that NDPPC has a binding affinity to p38⍺ MAP kinase similar to SB203580, a known inhibitor of p38α MAPK (Birkenkamp et al, 2000) (Figure 2).…”

Section: In Silico Target Prediction Revealed That Ndppc Is a Potent ...mentioning

confidence: 99%

“…Although the adult mammalian heart is recalcitrant to regeneration, recent findings indicate that stimulation of the CM cell cycle is a promising approach for inducing myocardial repair (Abouleisa et al, 2022;Johnson, Mohsin, & Houser, 2021;Salama, Gebreil, Mohamed, & Abouleisa, 2021). Our previous findings showed that overexpression of combined four cell cycle factors, CDK1, CDK4, cyclin B1, and cyclin D1 (collectively known as 4F), induced cell division in ~20% of the post-mitotic mouse, rat, and human CMs (Abouleisa et al, 2022;Mohamed et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Small Molecule Inhibitor of p38⍺ MAP Kinase Augments Cardiomyocyte Cell Cycle Entry in Response to Direct Cell Cycle Stimulation

Abouleisa

Miller

Gebreil

et al. 2023

Preprint

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Background and Purpose: Myocardial infarction (MI) is the leading cause of mortality globally due in part to the limited ability of cardiomyocytes (CMs) to regenerate. Recently, we demonstrated that overexpression of 4 cell cycle factors, CDK1, CDK4, cyclin B1, and cyclin D1 (4F), induced cell division in ~20% of the post-mitotic CMs overexpressed 4F. The current study aims to identify a small molecule that augments 4F-induced CM cycle induction. Experimental Approach, Key Results: Screening of small molecules with a potential to augment 4F-induced cell-cycle induction in 60-day-old mature human induced pluripotent cardiomyocytes (hiPS-CMs) revealed N-(4,6-Dimethylpyridin-2-yl)-4-(pyridin-4-yl)piperazine-1-carbothioamide (NDPPC), which activates cell cycle progression in 4F-transduced hiPS-CMs. Autodock tool and Autodock vina computational methods showed that NDPPC has a potential interaction with the binding site at the human p38⍺ mitogen-activated protein kinase (p38⍺ MAP kinase), a critical negative regulator of the mammalian cell cycle. A p38⍺ MAP kinase activity assay showed that NDPPC inhibits its activity in a dose-dependent manner. Overexpression of p38⍺ MAP kinase in CMs inhibited 4F cell cycle induction, and treatment with NDPPC reversed the cell cycle inhibitory effect. Conclusion and Implications: NDPPC is a novel inhibitor for p38⍺ MAP kinase and is a promising drug to augment CM cell cycle response to the 4F. NDPPC could become an adjunct treatment with other cell cycle activators for heart failure treatment.

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“…In contrast, complexes of cyclins/CDKs in adult mammalian CMs are constitutively inhibited by the CIP/KIP family (p21, p27, and p57) and the INK4 family (p16, p15, p18, and p19). Since the decline in the proliferative capacity of post-mitotic CMs might be due to the downregulation of cyclins/CDKs and upregulation of CIP/KIP family and INK4 family, whether the intervention with these cell-cycle regulators might induce CM cell-cycle entry has been widely investigated ( Salama et al, 2021 ). For example, overexpression of cyclin A2 in murine and porcine infarcted hearts improved heart function, and activated the cell cycle in CMs ( Woo et al, 2006 ; Cheng et al, 2007 ; Shapiro et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Manipulating Cardiomyocyte Plasticity for Heart Regeneration

Nomura

2022

Front. Cell Dev. Biol.

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Pathological heart injuries such as myocardial infarction induce adverse ventricular remodeling and progression to heart failure owing to widespread cardiomyocyte death. The adult mammalian heart is terminally differentiated unlike those of lower vertebrates. Therefore, the proliferative capacity of adult cardiomyocytes is limited and insufficient to restore an injured heart. Although current therapeutic approaches can delay progressive remodeling and heart failure, difficulties with the direct replenishment of lost cardiomyocytes results in a poor long-term prognosis for patients with heart failure. However, it has been revealed that cardiac function can be improved by regulating the cell cycle or changing the cell state of cardiomyocytes by delivering specific genes or small molecules. Therefore, manipulation of cardiomyocyte plasticity can be an effective treatment for heart disease. This review summarizes the recent studies that control heart regeneration by manipulating cardiomyocyte plasticity with various approaches including differentiating pluripotent stem cells into cardiomyocytes, reprogramming cardiac fibroblasts into cardiomyocytes, and reactivating the proliferation of cardiomyocytes.

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Induced Cardiomyocyte Proliferation: A Promising Approach to Cure Heart Failure

Cited by 12 publications

References 134 publications

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

A Novel Small Molecule Inhibitor of p38⍺ MAP Kinase Augments Cardiomyocyte Cell Cycle Entry in Response to Direct Cell Cycle Stimulation

Manipulating Cardiomyocyte Plasticity for Heart Regeneration

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