Muscle-Specific RING Finger 1 Negatively Regulates Pathological Cardiac Hypertrophy Through Downregulation of Calcineurin A

Q: What is the clinical evidence from this study?

Population: Cardiac hypertrophy. Intervention: MuRF1 knockout vs. Nontransgenic (NTg) mice. Primary outcome: Cardiac hypertrophy and left ventricular dysfunction.

Q: What does this research mean for the field?

Endogenous MuRF1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by directly ubiquitinating calcineurin A and suppressing calcineurin-NFAT signaling. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Yasuhiro Maejima; Soichiro Usui; Peiyong Zhai; Masayuki Takamura; Shuichi Kaneko; Daniela Zablocki; Mitsuhiro Yokota; Mitsuaki Isobe; Junichi Sadoshima

doi:10.1161/circheartfailure.113.000713

February 14, 2014Circulation Heart FailureOpen Access

Muscle-Specific RING Finger 1 Negatively Regulates Pathological Cardiac Hypertrophy Through Downregulation of Calcineurin A

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Key result

MuRF1 knockout exacerbates cardiac hypertrophy and LV dysfunction versus nontransgenic mice after transverse aortic constriction.

Why the study?

Does endogenous MuRF1 regulate pathological cardiac hypertrophy and dysfunction in response to pressure overload?

Key Points

To investigate the in vivo role and molecular mechanism of muscle-specific RING finger protein-1 (MuRF1) in modulating pressure overload-induced cardiac hypertrophy and dysfunction.
Subjected wild-type and MuRF1-knockout (Murf1-/-) mice to pressure overload induced by transverse aortic constriction (TAC) for 2 to 4 weeks.
Evaluated left ventricular function, cardiac fibrosis, apoptosis, and calcineurin-NFAT signaling activity using in vivo assays and in vitro cardiomyocyte ubiquitination analyses.
Crossbred Murf1-/- mice with cardiac-specific transgenic mice overexpressing ZAKI-4β, an endogenous calcineurin A inhibitor, to assess rescue of the phenotype.
Murf1-/- mice subjected to TAC displayed significantly more severe left ventricular dysfunction, hypertrophy, fibrosis, and apoptosis than non-transgenic control mice.
MuRF1 directly bound and polyubiquitinated calcineurin A, while MuRF1 deficiency stabilized calcineurin A protein levels and enhanced downstream NFAT luciferase reporter activity.
Cardiac-specific overexpression of ZAKI-4β reversed the augmented cardiac hypertrophy, ventricular dysfunction, fibrosis, and apoptosis observed in TAC-stressed Murf1-/- mice.

Structured PICO

Does endogenous MuRF1 regulate pathological cardiac hypertrophy and dysfunction in response to pressure overload?

P

Population

Mice subjected to transverse aortic constriction to induce pressure overload and evaluate the role of endogenous MuRF1.

I

Intervention

MuRF1 knockout (Murf1(-/-)) and cardiac-specific overexpression of ZAKI-4β

C

Comparator

Nontransgenic (NTg) mice

O

Outcome

Cardiac hypertrophy and left ventricular (LV) dysfunctionsurrogate

Endogenous MuRF1 negatively regulates pathological cardiac hypertrophy and dysfunction in response to pressure overload by inhibiting the calcineurin-NFAT pathway.

Implication

Suggests protective role for MuRF1 in pressure overload; hypothesis-generating for therapeutic targeting in human HF.

Discussion

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Cite This Study

Maejima et al. (2014) studied Cardiac hypertrophy. MuRF1 knockout vs. Nontransgenic (NTg) mice was evaluated on Cardiac hypertrophy and left ventricular dysfunction. MuRF1 knockout mice exhibited enhanced cardiac hypertrophy and left ventricular dysfunction compared with nontransgenic mice after transverse aortic constriction.

synapsesocial.com/papers/6aa4ce9b10877e4fda94e803 https://doi.org/10.1161/circheartfailure.113.000713

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Muscle-Specific RING Finger 1 Negatively Regulates Pathological Cardiac Hypertrophy Through Downregulation of Calcineurin A

Key Points

Structured PICO

Implication

Discussion

Cite This Study

Muscle-Specific RING Finger 1 Negatively Regulates Pathological Cardiac Hypertrophy Through Downregulation of Calcineurin A

Key Points

Structured PICO

Implication

Discussion

Cite This Study

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