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Published on: June 3, 2018
Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy
Daniel L Beckles1, Eduardo Mascareno, M A Q Siddiqui
1Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave. Brooklyn, NY 11203, USA.
Rationale:
We examined the role of Jak2 kinase phosphorylation in the development of pressure overload hypertrophy in mice subjected to transverse aortic constriction (TAC) and treated with tyrphostin AG490, a pharmacological inhibitor of Jak2.
Methods:
Control mice (sham), subjected to TAC for 15 days (TAC) or to TAC and treated with 48 microg/kg/day i.p. of tyrphostin AG490 (TAC+AG490) were evaluated for morphological, physiological, and molecular changes associated with pressure overload hypertrophy.
Results:
Mice subjected to TAC alone developed concentric hypertrophy that accompanied activation of the components of the Jak/STAT signaling pathway manifested by an increase in phosphorylation of Jak2 and STAT3. We also observed increased phosphorylation of MAPK p44/p42, p38 MAPK and JNK in the TAC group, as well as, an increase in expression of MKP-1 phosphatase which negatively regulates MAPK kinases. Treatment of aortic constricted mice with tyrphostin AG490 failed to develop hypertrophy and showed a marked reduction in phosphorylation of Jak2 and STAT3. There was, however, in TAC and AG490 treated mice, a notable increase in the phosphorylation state of the MAPK p44/42, whereas MKP-1 phosphatase was downregulated.
Conclusion:
These findings suggest that Jak2 kinase plays an important role in left ventricular remodeling during pressure overload hypertrophy. Pharmacological inhibition of Jak2 kinase during pressure overload blocks the development of concentric hypertrophy.
Insights
Inhibition of Jak2 kinase blocks the development of pressure overload hypertrophy in mice. This study highlights Jak2
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Signal Transduction
Background:
- Pressure overload hypertrophy is a significant cardiovascular condition.
- The Janus kinase 2 (Jak2) signaling pathway is implicated in cardiac remodeling.
- Understanding Jak2's role is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Jak2 kinase phosphorylation in pressure overload-induced cardiac hypertrophy.
- To evaluate the effects of tyrphostin AG490, a Jak2 inhibitor, on cardiac remodeling.
Main Methods:
- Mice underwent transverse aortic constriction (TAC) to induce pressure overload.
- Groups included sham controls, TAC, and TAC treated with tyrphostin AG490.
- Morphological, physiological, and molecular changes were assessed.
Main Results:
- TAC induced concentric hypertrophy and activated Jak/STAT signaling (increased Jak2 and STAT3 phosphorylation).
- MAPK pathway components (p44/42, p38, JNK) and MKP-1 phosphatase were altered in TAC mice.
- Tyrphostin AG490 treatment prevented hypertrophy, reduced Jak2/STAT3 phosphorylation, but increased MAPK p44/42 phosphorylation and downregulated MKP-1.
Conclusions:
- Jak2 kinase is a key mediator of left ventricular remodeling in pressure overload hypertrophy.
- Pharmacological inhibition of Jak2 effectively blocks the development of cardiac hypertrophy under pressure overload conditions.
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