Thyroid hormone (T3) plus dual-specificity phosphatase-5 siRNA therapy regenerates the myocardium lost as a result of doxorubicin cardiotoxicity

Abstract Doxorubicin is a widely used antineoplastic drug. However, its major side effect, cardiotoxicity, results from cardiomyocyte loss that causes left ventricle (LV) wall thinning, chronic LV dysfunction and heart failure. Here, we show that transient therapy with thyroid hormone (triiodothyronine, T3) and dual-specificity phosphatase-5 (DUSP5) siRNA results in cardiomyocyte proliferation. siRNA-directed depletion of DUSP5, a nuclear localized p-ERK1/2-specific phosphatase, sensitizes cardiomyocytes to the proliferative effects of T3 by potentiating p-ERK1/2 accumulation resulting from the activation of T3-mediated insulin-like growth factor-1 (IGF-1) signaling. In mice with chronic doxorubicin cardiotoxicity, this therapy regenerates the LV myocardium by cardiomyocyte proliferation, reverses LV dysfunction and prevents progressive chamber dilatation, providing a strategy for addressing a currently untreatable condition.

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Dual‐Specificity Phosphatase 26 Protects Against Cardiac Hypertrophy Through TAK1

Journal of the American Heart Association ◽

10.1161/jaha.119.014311 ◽

2021 ◽

Vol 10 (4) ◽

Author(s):

Jing Zhao ◽

Xiaoli Jiang ◽

Jinhua Liu ◽

Ping Ye ◽

Lang Jiang ◽

...

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Growth Factor ◽

Cardiac Hypertrophy ◽

Transforming Growth Factor ◽

Pressure Overload ◽

Transforming Growth Factor Β ◽

Kinase Signaling ◽

Dual Specificity Phosphatase ◽

Dual Specificity

Background Heart pathological hypertrophy has been recognized as a predisposing risk factor for heart failure and arrhythmia. DUSP (dual‐specificity phosphatase) 26 is a member of the DUSP family of proteins, which has a significant effect on nonalcoholic fatty liver disease, neuroblastoma, glioma, and so on. However, the involvement of DUSP26 in cardiac hypertrophy remains unclear. Methods and Results Our study showed that DUSP26 expression was significantly increased in mouse hearts in response to pressure overload as well as in angiotensin II–treated cardiomyocytes. Cardiac‐specific overexpression of DUSP26 mice showed attenuated cardiac hypertrophy and fibrosis, while deficiency of DUSP26 in mouse hearts resulted in increased cardiac hypertrophy and deteriorated cardiac function. Similar effects were also observed in cellular hypertrophy induced by angiotensin II. Importantly, we showed that DUSP26 bound to transforming growth factor‐β activated kinase 1 and inhibited transforming growth factor‐β activated kinase 1 phosphorylation, which led to suppression of the mitogen‐activated protein kinase signaling pathway. In addition, transforming growth factor‐β activated kinase 1–specific inhibitor inhibited cardiomyocyte hypertrophy induced by angiotensin II and attenuated the exaggerated hypertrophic response in DUSP26 conditional knockout mice. Conclusions Taken together, DUSP26 was induced in cardiac hypertrophy and protected against pressure overload induced cardiac hypertrophy by modulating transforming growth factor‐β activated kinase 1–p38/ c‐Jun N‐terminal kinase–signaling axis. Therefore, DUSP26 may provide a therapeutic target for treatment of cardiac hypertrophy and heart failure.

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DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

Scientific Reports ◽

10.1038/s41598-020-78825-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Nikolay Bogush ◽

Lin Tan ◽

Hussain Naib ◽

Ebrahim Faizullabhoy ◽

John W. Calvert ◽

...

Keyword(s):

Growth Factors ◽

Young Adult ◽

Growth Factor ◽

Thyroid Hormone ◽

Proliferative Response ◽

Cardiac Regeneration ◽

Left Ventricular ◽

Cardiomyocyte Proliferation ◽

Newborn Mice ◽

Dual Specificity

AbstractCardiomyocytes of newborn mice proliferate after injury or exposure to growth factors. However, these responses are diminished after postnatal day-6 (P6), representing a barrier to building new cardiac muscle in adults. We have previously shown that exogenous thyroid hormone (T3) stimulates cardiomyocyte proliferation in P2 cardiomyocytes, by activating insulin-like growth factor-1 receptor (IGF-1R)-mediated ERK1/2 signaling. But whether exogenous T3 functions as a mitogen in post-P6 murine hearts is not known. Here, we show that exogenous T3 increases the cardiomyocyte endowment of P8 hearts, but the proliferative response is confined to cardiomyocytes of the left ventricular (LV) apex. Exogenous T3 stimulates proliferative ERK1/2 signaling in apical cardiomyocytes, but not in those of the LV base, which is inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. Developmentally, between P7 and P14, DUSP5 expression increases in the myocardium from the LV base to its apex; after this period, it is uniformly expressed throughout the LV. In young adult hearts, exogenous T3 increases cardiomyocyte numbers after DUSP5 depletion, which might be useful for eliciting cardiac regeneration.

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Redox activation of JNK2α2 mediates thyroid hormone-stimulated proliferation of neonatal murine cardiomyocytes

Scientific Reports ◽

10.1038/s41598-019-53705-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Lin Tan ◽

Nikolay Bogush ◽

Hussain Naib ◽

Jennifer Perry ◽

John W. Calvert ◽

...

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Thyroid Hormone ◽

Early Response ◽

High Reactivity ◽

Specific Cell ◽

Activator Protein 1 ◽

Cardiomyocyte Proliferation ◽

Cell Functions ◽

Cell Cycle Activation

AbstractMitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H2O2). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H2O2 (mH2O2) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H2O2 that activates c-Jun N-terminal kinase-2α2 (JNK2α2). JNK2α2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation—this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.

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Nerve Growth Factor Stimulates Cardiac Regeneration via Cardiomyocyte Proliferation in Experimental Heart Failure

PLoS ONE ◽

10.1371/journal.pone.0053210 ◽

2012 ◽

Vol 7 (12) ◽

pp. e53210 ◽

Cited By ~ 17

Author(s):

Nicholas T. Lam ◽

Peter D. Currie ◽

Graham J. Lieschke ◽

Nadia A. Rosenthal ◽

David M. Kaye

Keyword(s):

Heart Failure ◽

Nerve Growth Factor ◽

Growth Factor ◽

Cardiac Regeneration ◽

Cardiomyocyte Proliferation ◽

Nerve Growth ◽

Experimental Heart Failure

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DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

10.21203/rs.3.rs-73803/v1 ◽

2020 ◽

Author(s):

Nikolay Bogush ◽

Lin Tan ◽

Hussain Naib ◽

Ebrahim Faizullabhoy ◽

John W. Calvert ◽

...

Keyword(s):

Thyroid Hormone ◽

Enzymatic Digestion ◽

Left Ventricular ◽

Lineage Tracing ◽

Cardiomyocyte Proliferation ◽

Dual Specificity ◽

M Phase ◽

Immunohistochemical Studies ◽

Regenerative Therapies

Abstract A developmental surge in thyroid hormone (T3) after postnatal day-10 (P10), in mice, results in a burst of cardiomyocyte proliferation. This finding remains controversial, which could arise from perceived homogeneity of myocardial sampling for immunoblotting and immunohistochemical studies, or from differences in enzymatic digestion efficiency for cardiomyocyte isolation used to determine total ventricular cardiomyocyte numbers. Using a highly efficient (>97%) method for cardiomyocyte isolation, we show that exogenous T3 administered in vivo to post-neonatal (after postnatal P6) mice increased cardiomyocyte numbers. Using S- and M-phase markers, and lineage-tracing tools to assay for cell cycle activation and cytokinesis, respectively, we show that the T3-mediated increase in cardiomyocytes is confined to cells of the left ventricular (LV) apex; such spatial heterogeneity also being observed during normal development, which might confound substantiation of developmental increases in cardiomyocyte proliferation. In these apical cardiomyocytes, T3 stimulates proliferative ERK1/2 signaling, whereas those in the LV base are tonically inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. In P21 Dusp5–/– mice, cardiomyocyte endowment and LV mass are increased relative to age-matched wild-type controls, suggesting that DUSP5 regulates early heart growth. Identification of mechanisms regulating cardiomyocyte proliferation may allow development of cardiac regenerative therapies.

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