Phosphodiesterases Expression during Murine Cardiac Development

Carvalho, Thays Maria da Conceição Silva; Cardarelli, Silvia; Giorgi, Mauro; Lenzi, Andrea; Isidori, Andrea M.; Naro, Fabio

doi:10.3390/ijms22052593

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…In several human and rodent tissues, a third isoform, Pde5a3 has been identified, which lacks the 5′ amino regions of the other two isoforms and starts from an ATG present in the second exon common to all the isoforms [38]. This isoform was not detectable in none of the murine skeletal muscle cells analyzed; however, Pde5a3 is clearly measurable in an embryonic mouse heart, decreases during development, and is present at low levels in a normal adult heart [48].…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology

Arcangelis

Angelis

Barbagallo

et al. 2022

IJMS

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Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of three different Pde5a isoforms in cardiomyocytes, and we have found that the expression of specific Pde5a isoforms may have a causal role in the onset of pathological responses in these cells. In our previous study, we demonstrated that PDE5A inhibition could ameliorate muscular dystrophy by acting at different levels, as assessed by the altered genomic response of muscular cells following treatment with the PDE5A inhibitor tadalafil. Thus, considering the importance of PDE5A in various pathophysiological conditions, we further investigated the regulation of this enzyme. Here, we analysed the expression of Pde5a isoforms in the pathophysiology of skeletal muscle. We found that skeletal muscle tissues and myogenic cells express Pde5a1 and Pde5a2 isoforms, and we observed an increased expression of Pde5a1 in damaged skeletal muscles, while Pde5a2 levels remained unchanged. We also cloned and characterized the promoters that control the transcription of Pde5a isoforms, investigating which of the transcription factors predicted by bioinformatics analysis could be involved in their modulation. In conclusion, we found an overexpression of Pde5a1 in compromised muscle and identified an involvement of MyoD and Runx1 in Pde5a1 transcriptional activity.

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Section: Discussionmentioning

confidence: 99%

Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology

Arcangelis

Angelis

Barbagallo

et al. 2022

IJMS

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“…Both cAMP and cGMP are important second messengers that regulate numerous signaling pathways and play a vital role in aging-related CVD (Lehners et al, 2018). Cyclic AMP is synthesized by adenylyl cyclases (ACs), and cGMP is produced from both the cytosolic soluble (sGC) and membrane-bound particulate guanylyl cyclases (pGC) (Carvalho et al, 2021). Activation of ACs and GCs in VSMCs occurs upon binding a myriad of different naturally occurring agonists to their receptors, of which respectively vasodilating prostaglandins (AC) and natriuretic peptides (pGC) are exemplary.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features

et al. 2022

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Age-related cardiovascular diseases (CVDs) remain among the leading global causes of death, and vascular smooth muscle cell (VSMC) remodeling plays an essential role in its pathology. Reduced NO-cGMP pathway signaling is a major feature and pathogenic mechanism underlying vasodilator dysfunction. Recently, we identified phosphodiesterase (PDE) 1, an enzyme that hydrolyzes and inactivates the cyclic nucleotides cAMP and cGMP, and thereby provides a potential treatment target for restoring age-related vascular dysfunction due to aging of VSMC. Based on this hypothesis, we here tested the effects of PDE1 inhibition in a model of SMC-specific accelerated aging mice. SMC-KO and their WT littermates received either vehicle or the PDE1 inhibitor lenrispodun for 8 weeks. Vascular function was measured both in vivo (Laser Doppler technique) and ex vivo (organ bath). Moreover, we deployed UV irradiation in cell culture experiments to model accelerated aging in an in vitro situation. SMC-KO mice display a pronounced loss of vasodilator function in the isolated aorta, the cutaneous microvasculature, and mesenteric arteries. Ex vivo, in isolated vascular tissue, we found that PDE1 inhibition with lenrispodun improves vasodilation, while no improvement was observed in isolated aorta taken from mice after chronic treatment in vivo. However, during lenrispodun treatment in vivo, an enhanced microvascular response in association with upregulated cGMP levels was seen. Further, chronic lenrispodun treatment decreased TNF-α and IL-10 plasma levels while the elevated level of IL-6 in SMC-KO mice remained unchanged after treatment. PDE1 and senescence markers, p16 and p21, were increased in both SMC-KO aorta and cultured human VSMC in which DNA was damaged by ultraviolet irradiation. This increase was lowered by chronic lenrispodun. In contrast, lenrispodun increased the level of PDE1A in both situations. In conclusion, we demonstrated that PDE1 inhibition may be therapeutically useful in reversing aspects of age-related VSMC dysfunction by potentiating NO-cGMP signaling, preserving microvascular function, and decreasing senescence. Yet, after chronic treatment, the effects of PDE1 inhibition might be counteracted by the interplay between differential PDE1A and C expression. These results warrant further pharmacodynamic profiling of PDE enzyme regulation during chronic PDE1 inhibitor treatment.

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Modulation of cAMP/cGMP signaling as prevention of congenital heart defects in Pde2A deficient embryos: a matter of oxidative stress

Cardarelli,

Biglietto,

Orsini

et al. 2024

Cell Death Dis

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Phosphodiesterase 2A (Pde2A) is a dual-specific PDE that breaks down both cAMP and cGMP cyclic nucleotides. We recently highlighted a direct relationship between Pde2A impairment, a consequent increase of cAMP, and the appearance of mouse congenital heart defects (CHDs). Here we aimed to characterize the pathways involved in the development of CHDs and in their prevention by pharmacological approaches targeting cAMP and cGMP signaling. Transcriptome analysis revealed a modulation of more than 500 genes affecting biological processes involved in the immune system, cardiomyocyte development and contractility, angiogenesis, transcription, and oxidative stress in hearts from Pde2A−/− embryos. Metoprolol and H89 pharmacological administration prevented heart dilatation and hypertabeculation in Pde2A−/− embryos. Metoprolol was also able to partially impede heart septum defect and oxidative stress at tissue and molecular levels. Amelioration of cardiac defects was also observed by using the antioxidant NAC, indicating oxidative stress as one of the molecular mechanisms underpinning the CHDs. In addition, Sildenafil treatment recovered cardiac defects suggesting the requirement of cAMP/cGMP nucleotides balance for the correct heart development.

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Phosphodiesterases Expression during Murine Cardiac Development

Cited by 4 publications

References 41 publications

Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology

Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology

The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features

Modulation of cAMP/cGMP signaling as prevention of congenital heart defects in Pde2A deficient embryos: a matter of oxidative stress

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