Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice

Liu, Huan; Chu, Shujuan; Wu, Zhilin

doi:10.1186/s12979-021-00251-y

Cited by 13 publications

(4 citation statements)

References 36 publications

(37 reference statements)

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“…Recent studies have reported that cardiac inflammation induced by Ang II may occur through the TLR4/MyD88/NF-κB and TLR4/TRIF/NF-κB pathways (14,19,32,39). NF-κB is a known transcription factor involved in TLR signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling

Theobald

Nair

Sriramula

et al. 2023

Front. Cardiovasc. Med.

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Toll-like receptor 4 (TLR4) is an integral factor in the initiation of the innate immune response and plays an important role in cardiovascular diseases such as hypertension and myocardial infarction. Previous studies from our lab demonstrated that central TLR4 blockade reduced cardiac TLR4 expression, attenuated hypertension, and improved cardiac function. However, the contribution of cardiac specific TLR4 to the development of hypertension and cardiac remodeling is unknown. Therefore, we hypothesized that cardiomyocyte specific knockdown of TLR4 would have beneficial effects on hypertension, cardiac hypertrophy, and remodeling. To test this hypothesis, cardiomyocyte-specific TLR4 knockdown (cTLR4KO) mice were generated by crossing floxed TLR4 mice with Myh6-Cre mice, and subjected to angiotensin II (Ang II, 1 µg/kg/min or vehicle for 14 days) hypertension model. Blood pressure measurements using radio telemetry revealed no differences in baseline mean arterial pressure between control littermates and cTLR4KO mice (103 ± 2 vs. 105 ± 3 mmHg, p > 0.05). Ang II-induced hypertension (132 ± 2 vs. 151 ± 3 mmHg, p < 0.01) was attenuated and cardiac hypertrophy (heart/body weight; 4.7 vs. 5.8 mg/g, p < 0.01) was prevented in cTLR4KO mice when compared with control mice. In addition, the level of myocardial fibrosis was significantly reduced, and the cardiac function was improved in cTLR4KO mice infused with Ang II. Furthermore, cardiac inflammation, as evidenced by elevated gene expression of TNF, IL-6, and MCP-1 in the left ventricle, was attenuated in cTLR4KO mice infused with Ang II. Together, this data revealed a protective role for cardiomyocyte-specific deletion of TLR4 against Ang II-induced hypertension and cardiac dysfunction through inhibition of proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling

Theobald

Nair

Sriramula

et al. 2023

Front. Cardiovasc. Med.

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“…Based on the broad multitissue rejuvenation by the old plasma dilution, we noted those pathways among the 43, which are known to be altered with aging in ways that interfere with the maintenance and repair of multiple tissues: the JAK-STAT [ 40 ], MAPK/ERK1/2 [ 41 ], TGF-beta [ 35 ], NF-κB [ 42 ], and Toll-like receptor signaling [ 43 ] (Fig. 3B and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Old plasma dilution reduces human biological age: a clinical study

Kim

Kiprov²,

Luellen

et al. 2022

GeroScience

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This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.

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“…These results suggest that immune cells TLR4 promote cardiac dysfunction in an endotoxemia model [103]. Loss of TLR4 in mice attenuated-aging-associated cardiovascular dysfunction by suppressing oxidative stress by upregulation of Cu-Zn superoxide dismutase (SOD1) and Manganes-SOD (SOD2) and downregulation of senescence markers p16 and p53 [118].…”

Section: Tlr4 Overexpression or Knockdown In Preclinical Models Of Ca...mentioning

confidence: 80%

TLR4—A Pertinent Player in Radiation-Induced Heart Disease?

Gawali

Sridharan

Krager

et al. 2023

Genes

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The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation several years post-radiotherapy. Moreover, the continued threat of nuclear bombs or terrorist attacks puts deployed military service members at risk of exposure to total or partial body irradiation. Individuals who survive acute injury from IR will experience delayed adverse effects that include fibrosis and chronic dysfunction of organ systems such as the heart within months to years after radiation exposure. Toll-like receptor 4 (TLR4) is an innate immune receptor that is implicated in several cardiovascular diseases. Studies in preclinical models have established the role of TLR4 as a driver of inflammation and associated cardiac fibrosis and dysfunction using transgenic models. This review explores the relevance of the TLR4 signaling pathway in radiation-induced inflammation and oxidative stress in acute as well as late effects on the heart tissue and the potential for the development of TLR4 inhibitors as a therapeutic target to treat or alleviate RIHD.

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Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice

Cited by 13 publications

References 36 publications

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling

Old plasma dilution reduces human biological age: a clinical study

TLR4—A Pertinent Player in Radiation-Induced Heart Disease?

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