# Phosphatidylinositol 4-Kinase IIIβ: A Therapeutic Target for Contractile Dysfunction in Hypertrophic Cardiomyocytes

## TL;DR

This study shows that inhibiting PI4KIIIβ can reduce glucose uptake and improve heart function in hypertrophic cardiomyocytes.

## Contribution

The paper introduces PI4KIIIβ as a novel therapeutic target for treating contractile dysfunction in hypertrophic cardiomyopathy.

## Key findings

- PI4KIIIβ inhibition reversed glucose uptake and contractile dysfunction in hypertrophic cardiomyocytes.
- Hypertrophic signaling and cell size were unaffected by PI4KIIIβ inhibition.
- Targeting PI4KIIIβ may offer a new strategy to treat contractile dysfunction without affecting hypertrophy itself.

## Abstract

Cardiac hypertrophy is an important risk factor for heart failure and is often accompanied by contractile dysfunction. While hypertrophic growth contributes to disease progression, the underlying molecular mechanisms remain incompletely understood. A proposed contributor is a metabolic shift toward glucose uptake, suggesting that kinases regulating this process, such as protein kinase D1 (PKD1) and downstream target phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), might be effective targets to mitigate cardiac hypertrophy-induced contractile dysfunction. We investigated whether PI4KIIIβ inhibition downregulates enhanced glucose uptake in hypertrophic cardiomyocytes and thereby treats cardiac hypertrophy-induced contractile dysfunction. Hypertrophy was induced in cultured adult rat cardiomyocytes and human stem cell-derived cardiomyocytes using either phenylephrine (PE) or adenoviral PKD1 overexpression. PE-induced hypertrophy was associated with increased mRNA expression of BNP, activation of hypertrophic signaling, morphological alterations, enhanced protein synthesis and glucose uptake, and impaired contractile function. Treatment with the PI4KIIIβ inhibitor MI14 prevented and reversed PE-stimulated glucose uptake and contractile dysfunction, while hypertrophic signaling, cell size, and protein synthesis remained unaffected. Similar effects on glucose uptake were observed in the PKD1 overexpression model. These findings suggest that targeting myocardial substrate metabolism via the PI4KIIIβ pathway, rather than hypertrophic growth itself, could be a promising strategy to treat hypertrophy-induced contractile dysfunction.