# The rewiring of cAMP/cGMP and LDH signalling drives cardiac hypertrophy in Pde5a−/− mice

## TL;DR

This study shows that Pde5a deficiency and inhibition affect cardiac hypertrophy differently, with implications for personalized treatment using Pde5a inhibitors.

## Contribution

The study reveals that Pde5a deficiency does not protect against cardiac hypertrophy and identifies metabolic rewiring involving cAMP/cGMP and LDH.

## Key findings

- Pde5a−/− mice developed cardiac hypertrophy similar to Pde5a+/+ mice after TAC.
- Sildenafil prevented moderate hypertrophy in Pde5a+/+ but not in Pde5a−/− mice.
- Metabolic remodelling in Pde5a−/− hearts involves a shift to mixed oxidative-glycolytic metabolism.

## Abstract

This discovery will be very useful in term of personalized medicine because Pde5a inhibitors should be administrated depending on the severity of cardiac hypertrophy. Moreover, the Pde5a/Sildenafil system counteracts a metabolic rewiring occurring in cardiac hypertrophy.

Phosphodiesterase type 5a (Pde5a), an enzyme that hydrolyzes cGMP nucleotide, regulates several aspects of heart physiology and its inhibition improves left ventricular heart function under pathological conditions. We investigated Pde5a role in the development and progression of moderate and severe cardiac hypertrophy, induced by transverse aortic constriction (TAC), in Pde5a WT (Pde5a+/+) and Pde5a-deficient (Pde5a−/−) mice. Cardiac hypertrophy was surprisingly detected in Pde5a−/− mice after TAC surgery with similar alterations of cardiac function, morphology, fibrosis, and expression of molecular markers compared with Pde5a+/+ mice. The Pde5a inhibitor, Sildenafil, prevented only moderate cardiac hypertrophy at the morpho-functional and molecular levels in Pde5a+/+ mice. Cardiac hypertrophy was found to be associated with unbalanced cAMP/cGMP ratio and lactate dehydrogenase plays a critical role in the metabolic remodelling of Pde5a−/− hearts under TAC conditions. In conclusion, pharmacological Pde5a inhibition counteracts moderate but not severe hypertrophy. Genetic ablation of Pde5a does not protect against moderate/severe cardiac hypertrophy. In the absence of Pde5a, the oxidative metabolism shifts towards a mixed oxidative-glycolytic metabolism under TAC condition.