Therapeutic Potential of Pde Modulation in Treating Heart Disease

Abstract

Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed.

Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes

“…Our analysis has revealed increased expression of genes implicated in heart disease including CLDN5, VWF, PDE6H, ITGA2B, and CA3 (80, 82, 83, 139, 140), as well as megakaryocyte differentiation (RGS18, GFI1B, and ARHGEF4 (75, 76)). ITGA2B is used as a biomarker for myocardial infarction risk and therapeutic modulation of phosphodiesterases is one strategy for treating cardiovascular disease.…”

From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure

“…Altered cyclic nucleotide-mediated signalling plays a critical role in the development of cardiovascular pathology, and is regulated by the action or inhibition of PDEs [79]. Altered expression of PDEs and cyclic nucleotide signalling have been implicated in a number of cardiovascular diseases, thus the pharmacological inhibition of PDEs has gained interest as an area for drug development for the treatment of HF.…”

“…However, a number of clinical trials have revealed chronic treatment with PDE3 inhibitors in heart failure patients is associated with increased mortality. Thus PDE3 inhibitors are now only used in patients with severe heart failure or those awaiting cardiac transplant (see review [79]). PDE5 expression is highly upregulated in the heart in response to pathological conditions and modulates cyclic GMP activity in the heart.…”

“…PDE5 expression is highly upregulated in the heart in response to pathological conditions and modulates cyclic GMP activity in the heart. PDE5 inhibitors such as sildenafil have been investigated as potential therapeutic agents in preclinical models (see review [79]). In a mouse model of myocardial pressure overload, inhibition of PDE5 with sildenafil attenuated cardiac hypertrophy and fibrosis, preserved cardiac function, and was associated with deactivation of various hypertrophy signalling cascades [80].…”

“…In a mouse model of myocardial pressure overload, inhibition of PDE5 with sildenafil attenuated cardiac hypertrophy and fibrosis, preserved cardiac function, and was associated with deactivation of various hypertrophy signalling cascades [80]. Sildenafil has been tested in a number of clinical trials indicating that PDE5 inhibitor treatment does appear to have beneficial effects on several forms of HF, including improved cardiac performance, reduced levels of inflammatory markers and a tolerable safety profile (see review [79]).…”