Cardiomyocyte-specific regression of nitrosative stress-mediated S-Nitrosylation of IKKγ alleviates pathological cardiac hypertrophy

Authors

Ratul Datta Chaudhuri, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address: dc.ratul@gmail.com.
Ritwik Datta, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address: rdatta30@gmail.com.
Santanu Rana, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address: rana.santanu@gmail.com.
Abhik Kar, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address: kar.abhik93@gmail.com.
Phuc Vinh Nguyen Lam, The Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA. Electronic address: phuclam87@gmail.com.
Raja Mazumder, The Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA. Electronic address: mazumder@gwu.edu.
Sujata Mohanty, Stem Cell Facility, DBT-Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: drmohantysujata@gmail.com.
Sagartirtha Sarkar, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India. Electronic address: sagartirtha.sarkar@gmail.com.

Document Type

Journal Article

Publication Date

7-11-2022

Journal

Cellular signalling

Volume

98

DOI

10.1016/j.cellsig.2022.110403

Keywords

Cardiac hypertrophy; IKKγ; Myocyte regeneration; Nitric oxide; S-Nitrosylation

Abstract

IKKγ prototypically promotes NFκBp65 activity by regulating the assembly of the IKK holocomplex. In hypertrophied cardiomyocytes, the p65-p300 complex-induced regenerative efforts are neutralized by the p53-p300 complex-mediated apoptotic load resulting in compromised cardiac function. The present study reports that nitrosative stress leads to S-Nitrosylation of IKKγ in hypertrophied cardiomyocytes in a pre-clinical model. Using a cardiomyocyte-targeted nanoconjugate, IKKγ S-Nitrosylation-resistant mutant plasmids were delivered to the pathologically hypertrophied heart that resulted in improved cardiac function by amelioration of cardiomyocyte apoptosis and simultaneous induction of their cell cycle re-entry machinery. Mechanistically, in IKKγ S-Nitrosyl mutant-transfected hypertrophied cells, increased IKKγ-p300 binding downregulated the binding of p53 and p65 with p300. This shifted the binding preference of p65 from p300 to HDAC1 resulting in upregulated expression of cyclin D1 and CDK2 via the p27/pRb pathway. This approach has therapeutic advantage over mainstream anti-hypertrophic remedies which concomitantly reduce the regenerative prowess of resident cardiomyocytes during hypertrophy upon downregulation of myocyte apoptosis. Therefore, cardiomyocyte-targeted delivery of IKKγ S-Nitrosyl mutants during hypertrophy can be exploited as a novel strategy to re-muscularize the diseased heart.

APA Citation

Datta Chaudhuri, Ratul; Datta, Ritwik; Rana, Santanu; Kar, Abhik; Vinh Nguyen Lam, Phuc; Mazumder, Raja; Mohanty, Sujata; and Sarkar, Sagartirtha, "Cardiomyocyte-specific regression of nitrosative stress-mediated S-Nitrosylation of IKKγ alleviates pathological cardiac hypertrophy" (2022). GW Authored Works. Paper 1321.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1321

Department

Biochemistry and Molecular Medicine