Related Experiment Video
Updated: Jan 8, 2026
In vitro Assessment of Cardiac Reprogramming by Measuring Cardiac Specific Calcium Flux with a GCaMP3 Reporter
Published on: February 22, 2022
Targeting of Cdc42-Interacting Protein 4-Calcineurin Signalosomes Improves Cardiac Structure and Function After
Anne-Maj Samuelsson1, Abraham L Bayer2, Jinliang Li1
1Departments of Ophthalmology and Medicine Stanford Cardiovascular Institute, Stanford University Palo Alto CA USA.
Background:
CaN (calcineurin) promotes pathological cardiac remodeling but also cardioprotection in ischemia-reperfusion injury. CaN inhibitors are also immunosuppressants. This pleiotropy complicates targeting calcineurin in cardiovascular disease. CIP4/TRIP10 (Cdc42-interacting protein 4) is a scaffold protein that binds the CaNAβ (calcineurin Aβ) N-terminal polyproline domain and organizes a calcium and CaNAβ2 signaling compartment independent of contractile calcium. We showed that CIP4-CaNAβ2 signalosomes promote pathological cardiac hypertrophy induced by pressure overload. It is unknown whether CIP4-CaNAβ2 signalosomes contribute to cardioprotection and remodeling in ischemic disease.
Methods:
CIP4 conditional knockout mice were studied following ischemia-reperfusion and permanent left coronary artery ligation that induce myocardial infarction. C57BL/6NJ mice were transduced with cardiotropic adeno-associated virus expressing a CaNAβ2 small hairpin RNA to inhibit CaNAβ2 expression, a VIVIT peptide to inhibit CaN-NFAT (nuclear factor of activated T cells) signaling, or a CaNAβ polyproline peptide to block CIP4-CaNAβ2 binding and similarly studied by ischemia-reperfusion injury and left coronary artery ligation. CaNAβ polyproline-dependent signaling was also studied in T cells.
Results:
CIP4 conditional knockout and cardiomyocyte-specific CaNAβ polyproline peptide expression improved cardiac function after ischemia-reperfusion injury and decreased infarct size and improved cardiac function after permanent left coronary artery ligation. In contrast, cardiomyocyte-specific CaNAβ2 depletion and VIVIT expression worsened outcome after myocardial infarction. The polyproline peptide had no effect on T-cell activation and cytokine expression in vitro.
Conclusions:
CIP4-CaNAβ2 signalosomes promote adverse cardiac remodeling and are not cardioprotective. Proof of concept is provided for the treatment of ischemic cardiomyopathy by a polyproline peptide gene therapy. Targeting these complexes may be beneficial in cardiovascular diseases, including ischemic cardiomyopathy and acute myocardial infarction.
Insights
Targeting CIP4-CaNAβ2 signalosomes with a polyproline peptide shows promise for treating ischemic cardiomyopathy. This approach improves cardiac function and reduces infarct size in myocardial infarction models.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Signal Transduction
Background:
- Calcineurin (CaN) has dual roles in cardiac remodeling and ischemia-reperfusion injury.
- CIP4/TRIP10 scaffold protein forms CaNAβ2 signaling compartments.
- CIP4-CaNAβ2 signalosomes drive pathological cardiac hypertrophy.
Purpose of the Study:
- Investigate the role of CIP4-CaNAβ2 signalosomes in ischemic heart disease.
- Determine if these signalosomes contribute to cardioprotection or adverse remodeling.
- Evaluate therapeutic potential of targeting CIP4-CaNAβ2 interactions.
Main Methods:
- Utilized CIP4 conditional knockout mice.
- Employed adeno-associated virus gene therapy in mice to inhibit CaNAβ2 or block CIP4-CaNAβ2 binding.
- Assessed outcomes following ischemia-reperfusion injury and myocardial infarction.
Main Results:
- CIP4 knockout and polyproline peptide treatment improved cardiac function and reduced infarct size post-myocardial infarction.
- CaNAβ2 depletion and VIVIT peptide worsened outcomes in myocardial infarction models.
- The polyproline peptide did not affect T-cell activation in vitro.
Conclusions:
- CIP4-CaNAβ2 signalosomes promote adverse cardiac remodeling and are not cardioprotective.
- Polyproline peptide gene therapy offers a potential treatment for ischemic cardiomyopathy.
- Targeting these complexes may benefit patients with ischemic cardiomyopathy and acute myocardial infarction.
More Related Videos
08:03Ultrasound-Guided Induced Pluripotent Stem Cell-Derived Cardiomyocyte Implantation in Myocardial Infarcted Mice
Published on: March 30, 2022
14:35Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021