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Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure
Di Zhu1, Zhen Zhang1, Jianli Zhao1
1Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (D.Z., Z.Z., J.Z., D.L., L.G., W.B.L., D.X., Z.M., P.Y., J.T., T.A.C., B.L.L., Y.W., X.-L.M.).
Circulation Research
|May 25, 2022
Summary
Blocking adiponectin receptor 1 (AdipoR1) phosphorylation at Ser205 restores its protective signaling, reversing heart failure after myocardial infarction (MI). This approach, combined with adiponectin (APN) administration, offers a novel therapy for ischemic heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Pharmacology
Background:
- Ischemic heart failure remains a significant clinical challenge despite reduced acute myocardial infarction mortality.
- Pathological remodeling post-myocardial infarction requires effective therapeutic interventions.
- Adiponectin receptor 1 (AdipoR1) phosphorylation by GRK2 contributes to maladaptive cardiac remodeling.
Purpose of the Study:
- To elucidate mechanisms of AdipoR1 phosphorylative desensitization.
- To investigate if blocking AdipoR1 phosphorylation can restore its protective signaling.
- To evaluate the therapeutic potential of inhibiting AdipoR1 phosphorylation in reversing post-MI remodeling.
Main Methods:
- In vitro studies using neonatal and adult cardiomyocytes to identify AdipoR1 phosphorylation sites and mechanisms.
- In vivo studies in AdipoR1 knockout mice to assess the effects of AdipoR1 phosphorylation inhibition on post-MI remodeling and heart failure.
- Utilized site-directed mutagenesis (S205A, S205E) and pharmacological adiponectin (APN) administration.
Main Results:
- Phosphorylation of AdipoR1 at Ser205 by GRK2 leads to its endocytosis and lysosomal degradation, suppressing protective signaling.
- Mutating Ser205 to alanine (AdipoR1S205A) prevented GRK2-mediated suppression, restoring AdipoR1 function and APN-induced cardioprotection.
- In vivo, AdipoR1S205A expression preserved AdipoR1 function during heart failure, and APN administration reversed remodeling and improved cardiac function.
Conclusions:
- Serine 205 is critical for AdipoR1 desensitization in the failing heart.
- Blocking AdipoR1 phosphorylation represents a novel therapeutic strategy.
- Combined AdipoR1 phosphorylation blockade and APN administration effectively reverses post-MI remodeling and mitigates heart failure.
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