The rewiring of cAMP/cGMP and LDH signalling drives cardiac hypertrophy in Pde5a−/− mice
Ana Gabriela de Oliveira do Rêgo, Sonia Maccari, Giuseppe Marano, Tonino Stati, Michele Saliola, Mauro Giorgi, Silvia Cardarelli, Matilde Merolle, Francesco Tomassoni-Ardori, Lino Tessarollo, Federica Campolo, Andrea M Isidori, Luciana De Angelis, Fabio Naro, Lucia Monaco
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.
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…
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Taxonomy
TopicsPhosphodiesterase function and regulation · Nitric Oxide and Endothelin Effects · Heart Failure Treatment and Management