A diet abundant in sugar and fats derived from animal sources and cheap vegetable oils has been termed the """"""""Western diet"""""""". Consumption of the Western diet is now prevalent in the United States and has been spreading throughout the world over the past 15 years. Consumption of a Western style diet is implicated in the etiology of erectile dysfunction (ED), a condition strongly associated with reduced quality of life. Nitric oxide is a primary mediator of penile erection, which is produced by nitric oxide synthase. Under conditions of excessive oxidative stress, endothelial nitric oxide synthase (eNOS) may become uncoupled, whereby superoxide is produced rather than nitric oxide, which propagates further oxidative stress. It is thought that eNOS coupling status is regulated by adequate presence of co-factors and substrates. However, recent data indicate that eNOS uncoupling and dysfunctionality may be promoted by S-nitrosylation, which may be dependent on an oxidative shift in cellular redox state. Additionally, the mammalian target of rapamycin (mTOR) is a cellular signaling molecule that may induce oxidative stress in response to excessive fat and sugar consumption. The primary hypothesis of this proposal is that an oxidative shift in the penile redox environment, mediated by mTOR- dependent nutrient signaling in response to the Western diet promotes erectile dysfunction due to eNOS dysregulation via excessive S-nitrosylation induced by impairment of the denitrosylation system.
Specific aims for the proposal are: 1) to determine if Western diet-induced ED is mediated by an oxidative shift in redox state dependent upon mTOR signaling;2) to determine if the mTOR dependent shift in redox state exerts alteration of S-nitrosylation;3) to determine if regulation of S-nitrosylation controls erectile function in a diet-dependent manner. The proposed research plan includes the use of a Western style rodent diet in combination with pharmacologic, molecular, proteomic, and physiological studies. These studies utilize the Western diet in combination with pharmacologic shifts in redox state, inhibition of mTOR, and genetic manipulation of proteins that regulate denitrosylation. Molecular studies proposed include assessment of protein structure, function, and post-translational modifications influencing eNOS, the mTOR signaling pathway, and the proteins that regulate cellular S-nitrosylation. Proteomic studies proposed include assessment of S-nitrosylation status of the penile proteome, as well as S-nitrosylation of individual thiol groups of penile eNOS. Molecular and proteomic studies will be enriched by physiologic erectile function measurements in response to these perturbations. The proposed studies include the use of a genetic mouse model where the regulation of S-nitrosylation is manipulated, and a rat model where the regulation of S-nitrosylation is manipulated specifically in the penis. It is anticipated that the findings of this proposal will provide greater understanding of molecular events leading to Western diet associated ED, and provide a basis for enhanced treatment.

Public Health Relevance

This project addresses mechanistic pathways by which an unhealthy, Western style diet promotes erectile dysfunction. Erectile dysfunction severely reduces quality of life, which is a major concern as Western diet consumption becomes increasingly prevalent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK100082-01A1
Application #
8717081
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rankin, Tracy L
Project Start
2014-09-24
Project End
2017-09-23
Budget Start
2014-09-24
Budget End
2015-09-23
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Karakus, Serkan; Musicki, Biljana; La Favor, Justin D et al. (2017) cAMP-dependent post-translational modification of neuronal nitric oxide synthase neuroprotects penile erection in rats. BJU Int 120:861-872
La Favor, Justin D; Burnett, Arthur L (2016) A microdialysis method to measure in vivo hydrogen peroxide and superoxide in various rodent tissues. Methods 109:131-140
La Favor, Justin D; Dubis, Gabriel S; Yan, Huimin et al. (2016) Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase: Influence of Exercise Training. Arterioscler Thromb Vasc Biol 36:2412-2420
Musicki, Biljana; Lagoda, Gwen; Goetz, Tabitha et al. (2016) Transnitrosylation: A Factor in Nitric Oxide-Mediated Penile Erection. J Sex Med 13:808-814