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Nitric Oxide-cGMP-PKG Signaling in the Cardioprotective Effects of Phosphodiesterase 5 Inhibitors

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Nitric Oxide: From Research to Therapeutics

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 22))

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Abstract

Phosphodiesterase 5 (PDE5) is an enzyme that catalyzes the degradation of cGMP to its inactive form, 5′-GMP. The inhibition of PDE5 leads to the increase in bioavailability of cGMP which exerts its downstream signaling effects through the activation of protein kinase G (PKG). The dysregulation of cGMP-PKG signaling cascade plays a critical role in the pathology of several cardiovascular disorders. PDE5 inhibitors including sildenafil and tadalafil are widely prescribed drugs for the treatment of erectile dysfunction and pulmonary hypertension in patients. In the pre-clinical setting, treatment with PDE5 inhibitors protect against several cardiovascular pathologies including ischemia/reperfusion (I/R) injury, heart failure, pressure overload-induced hypertrophy, and cardiomyopathy associated with type 2 diabetes and metabolic syndrome. Mechanistic studies reveal that nitric oxide (NO)-cGMP-PKG signaling driven multiple signaling pathways are involved in protection against most of these pathologies. Moreover, the PDE5 inhibitors generate other gasotransmitters including hydrogen sulfide, carbon monoxide in addition to NO that may play a critical role in cardioprotection.

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Acknowledgements

This work was supported by Grants from the National Institutes of Health RO1HL134366 (RCK & AD), R37 HL-51045, RO1HL118808, R01CA221813, R01DK120866 (RCK).

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Authors and Affiliations

  1. Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA

    Rakesh C. Kukreja, Anindita Das, Saisudha Koka, Arun Samidurai & Lei **

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  1. Rakesh C. Kukreja
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  2. Anindita Das
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  3. Saisudha Koka
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  4. Arun Samidurai
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  5. Lei **
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Correspondence to Rakesh C. Kukreja .

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Editors and Affiliations

  1. Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, Hamdard University, New Delhi, India

    Arunabha Ray

  2. Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India

    Kavita Gulati

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Kukreja, R.C., Das, A., Koka, S., Samidurai, A., **, L. (2023). Nitric Oxide-cGMP-PKG Signaling in the Cardioprotective Effects of Phosphodiesterase 5 Inhibitors. In: Ray, A., Gulati, K. (eds) Nitric Oxide: From Research to Therapeutics. Advances in Biochemistry in Health and Disease, vol 22. Springer, Cham. https://doi.org/10.1007/978-3-031-24778-1_6

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