P16ink4a overexpression ameliorates cardiac remodeling of mouse following myocardial infarction via CDK4/pRb pathway

Shi, Jianzhou; Sun, Junran; Liu, Liu; Shan, Tiankai; Meng, Haoyu; Yang, Tongtong; Wang, Sibo; Wei, Tianwen; Chen, Bingrui; Ma, Yao; Wang, Qiming; Wang, Hao; Liu, Jiabao; Wang, Liansheng

doi:10.1016/j.bbrc.2022.01.077

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…Forced overexpression of p16INK4A improved cardiac function while silencing of p16INK4A deteriorated cardiac function. As a possible underlying mechanism, reduced fibroblast proliferation, and collagen accumulation and less cardiac fibrosis was attributed to the classical cell-cycle inhibitory function of p16INK4A [ 213 ]. Increased cardiomyocyte proliferation and better functional recovery after MI has been reported in p16INK4A knockout mice [ 144 ].…”

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

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It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

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Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

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“…Ad5:cTNT-CON served as an empty control virus for Ad5:cTNT-INK4a and Ad5:cTNT-INK4a RNAi. It was found in previous studies of primary CMs in vitro that we used a multiplicity of infection (MOI) = 50 as a viral titer to transfect CMs 48 hours after performing other relevant experimental assays [ 17 , 21 ]. In vivo, 1-day-old neonatal mice underwent AR + intramyocardial injection: Ad5:cTNT-INK4a RNAi (3.0 × 10 7 PFU/mouse, total volume = 6 μ l/mouse) or Ad5-cTNT-CON (3.0 × 10 7 PFU/mouse, total volume = 6 μ l/mouse).…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, cooverexpression of p16 INK4a and p21 WAF1 inhibited Ang II-induced CMs hypertrophy [ 15 ]; p16 INK4a knockdown inhibited the PDGFB and TWIST1 expression in pulmonary arterial hypertension and subsequent vascular remodelling [ 16 ]. In addition, our previous research demonstrated that timely p16 INK4a overexpression could restrain the proliferation of cardiac fibroblasts, thus inhibiting the myocardial fibrosis process [ 17 ]. However, whether p16 INK4a functions in CMs during the regenerative repair deserves further investigation.…”

Section: Introductionmentioning

confidence: 99%

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

Sun

Zhou

Yang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Neonatal mice achieve complete cardiac repair through endogenous myocardial regeneration after apical resection (AR), but this capacity is rapidly lost 7 days after birth. As an upstream inhibitor of cyclin-dependent kinase 4/6- (CDK4/6-) mediated cell cycle activity, p16INK4a is widely involved in regulating tumor and senescence. Given that p16INK4a had a significant negative regulation on cell proliferation, targeting cardiomyocytes (CMs) to inhibit p16INK4a seems to be a promising attempt at myocardial regeneration therapy. The p16INK4a expression was upregulated during perimyocardial regeneration time. Knockdown of p16INK4a stimulated CM proliferation, while p16INK4a overexpression had the opposite effect. In addition, p16INK4a knockdown prolonged the proliferation time window of newborn myocardium. And p16INK4a overexpression inhibited cell cycle activity and deteriorated myocardial regeneration after AR. The quantitative proteomic analysis showed that p16INK4a knockdown mediated the cell cycle progression and intervened in energy metabolism homeostasis. Mechanistically, overexpression of p16INK4a causes abnormal accumulation of reactive oxygen species (ROS) to induce autophagy, while scavenging ROS with N-acetylcysteine can alleviate autophagy and regulate p16INK4a, CDK4/6, and CyclinD1 in a covering manner. And the effect of inhibiting the proliferation of p16INK4a-activated CMs was significantly blocked by the CDK4/6 inhibitor Palbociclib. In summary, p16INK4a regulated CM proliferation progression through CDK4/6 and ROS-related autophagy to jointly affect myocardial regeneration repair. Our study revealed that p16INK4a might be a potential therapeutic target for myocardial regeneration after injury.

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“…The CFs were treated with Ang II (1 mmol/L) for 48 h (Sigma, St. Louis, MO, USA) to establish the cellular model of cardiac fibrosis in the presence or absence of TRIM33/HSPB5 overexpression plasmids and TRIM33 shRNA. RNA transfection was performed according to the manufacturer’s instructions by using Lipofectamine 2000 Transfection Reagent (Invitrogen) [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

The crystallin alpha B (HSPB5)-tripartite motif containing 33 (TRIM33) axis mediates myocardial fibrosis induced by angiotensinogen II through transforming growth factor-β (TGF-β1)-Smad3/4 signaling

Wei

Shan

et al. 2022

Bioengineered

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Myocardial fibrosis, a common pathological manifestation of cardiac remodeling (CR), often leads to heart failure (HF) and even death. The underlying molecular mechanism of the role of TRIM33 in Ang II–induced myocardial fibrosis is not fully understood. We found that TRIM33 was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. Adult mice induced by Ang II were used as in vivo models, and Ang II–induced neonatal mouse primary cardiac fibroblasts (CFs) were used as in vitro models. The level of CF fibrosis in vitro was assessed by CF proliferation, migration, activation and extracellular matrix (ECM) synthesis. In addition, Masson staining, the heart weight/body weight (HW/BW) ratio and echocardiography were used to evaluate the in vivo effect of TRIM33. TRIM33 expression was specifically upregulated in CFs and myocardial tissue after Ang II stimulation. In in vitro experiments, we found that TRIM33 knockdown promoted Ang II–induced CF proliferation, while TRIM33 overexpression weakened Ang II–induced CF proliferation, migration, activation and collagen synthesis. Mechanistically, we showed that TRIM33, negatively regulated by HSPB5, mediated its antifibrotic effect by inhibiting the activation of TGF-β1 and its downstream genes, Smad3 and Smad4. Finally, TRIM33 overexpression suppressed fibrosis and promoted cardiac repair and functional recovery in Ang II–induced mice. Our results clearly establish that TRIM33 limits cardiac fibrosis by hindering CF proliferation, migration, activation and collagen synthesis. Enhancing these beneficial functions of TRIM33 by a targeting vector might be a novel therapeutic strategy for CR.

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P16ink4a overexpression ameliorates cardiac remodeling of mouse following myocardial infarction via CDK4/pRb pathway

Cited by 10 publications

References 36 publications

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

The crystallin alpha B (HSPB5)-tripartite motif containing 33 (TRIM33) axis mediates myocardial fibrosis induced by angiotensinogen II through transforming growth factor-β (TGF-β1)-Smad3/4 signaling

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