The CIP protein is a modifier of dystrophic cardiomyopathy, according to a new study published in Molecular Therapy. It can, therefore, be a potential therapeutic target in cardiomyopathy due to Duchenne muscular dystrophy (DMD) and other dystrophic cardiomyopathies.

The authors of the study previously demonstrated that the CIP protein plays an important role in heart function. In the present study, they found it is also involved in the regulation of dystrophic cardiomyopathy.

Using a mouse model of DMD, the team led by Da-Zhi Wang, PhD, professor of pediatrics at Harvard Medical School, Boston, Massachusetts, found that the deletion of CIP led to dilated cardiomyopathy and heart failure. In a reverse experiment, the team showed that when they overexpressed CIP in syndromic animals, pathological dystrophic cardiomyopathy was reduced.

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Using genome-wide transcriptome analyses, the researchers showed that fibrogenesis and oxidative stress were affected in CIP-mediated dystrophic cardiomyopathy.

They also showed that CIP interacted with dystrophin, the protein that is missing in DMD, and calcineurin, a calcium-dependent serine-threonine phosphatase that activates T cells. This interaction suppresses the calcineurin-NFAT pathway, which normally regulates gene expression in response to changes in the concentration of intracellular calcium, and results in decreased Nox4 expression. 

Nox4 is a key component in the oxidative stress pathway. When it is overexpressed in DMD mice, the development of dystrophic cardiomyopathy is accelerated. Therefore, when the expression of Nox4 is downregulated via CIP, the development of dystrophic cardiomyopathy may be delayed or even prevented. 

Dystrophic cardiomyopathy is the leading cause of death in patients with DMD, and novel therapies are urgently needed.

According to the authors, with improvements in gene therapy approaches using adeno-associated virus (AAV) vectors, the CIP transgene could be specifically delivered to the heart in patients with DMD to treat dystrophic cardiomyopathy in the not-so-distant future.

Reference

He X, Liu J, Gu F, et al. Cardiac CIP protein regulates dystrophic cardiomyopathy. Mol Ther. Published online August 13, 2021. doi:10.1016/j.ymthe.2021.08.022

Neurologists