de Oliveira do Rêgo Ana Gabriela, Maccari Sonia, Marano Giuseppe, Stati Tonino, Saliola Michele, Giorgi Mauro, Cardarelli Silvia, Merolle Matilde, Tomassoni-Ardori Francesco, Tessarollo Lino, Campolo Federica, Isidori Andrea M, De Angelis Luciana, Naro Fabio, Monaco Lucia, Pellegrini Manuela
Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.
Institute of Biochemistry and Cell Biology, IBBC-CNR, Rome, Italy.
Life Sci Alliance. 2025 Jul 14;8(10). doi: 10.26508/lsa.202403094. Print 2025 Oct.
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 ( ) and Pde5a-deficient ( ) mice. Cardiac hypertrophy was surprisingly detected in mice after TAC surgery with similar alterations of cardiac function, morphology, fibrosis, and expression of molecular markers compared with mice. The Pde5a inhibitor, Sildenafil, prevented only moderate cardiac hypertrophy at the morpho-functional and molecular levels in 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 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.
5型磷酸二酯酶a（Pde5a）是一种水解环磷酸鸟苷（cGMP）核苷酸的酶，它调节心脏生理的多个方面，在病理条件下抑制该酶可改善左心室心脏功能。我们研究了Pde5a在由主动脉缩窄（TAC）诱导的中度和重度心脏肥大的发生和发展过程中的作用，实验对象为Pde5a野生型（ ）和Pde5a基因缺陷型（ ）小鼠。令人惊讶的是，在TAC手术后的 小鼠中检测到了心脏肥大，与 小鼠相比，其心脏功能、形态、纤维化及分子标志物表达均有类似改变。Pde5a抑制剂西地那非仅在形态功能和分子水平上预防了 小鼠的中度心脏肥大。研究发现，心脏肥大与cAMP/cGMP比例失衡有关，并且乳酸脱氢酶在TAC条件下 小鼠心脏的代谢重塑中起关键作用。总之，药物抑制Pde5a可对抗中度而非重度肥大。Pde5a基因敲除并不能预防中度/重度心脏肥大。在缺乏Pde5a的情况下，TAC条件下氧化代谢会转向混合氧化-糖酵解代谢。
