Sildenafil (Viagra) Aggravates the Development of Experimental Abdominal Aortic Aneurysm.
Chongyang ZhangAmy MohanHangchuan ShiChen YanPublished in: Journal of the American Heart Association (2022)
Background cGMP-hydrolyzing phosphodiesterase type 5 (PDE5) regulates vascular smooth muscle cell (SMC) contraction by antagonizing cGMP-dependent protein kinase I (PKGI)-dependent SMC relaxation. SMC contractile dysfunction is implicated in the pathogenesis of aortic aneurysm. PDE5 inhibitors have been used for treating erectile dysfunction, such as drug Viagra (sildenafil). However, a few clinical cases have reported the association of Viagra usage with aortic dissection, and reduced PDE5A expression was found in human aortic aneurysm tissues. Therefore, we aimed to investigate the effect of sildenafil on experimental abdominal aortic aneurysm (AAA), the most common form of aortic aneurysm in elderly men. Methods and Results AAA was induced in C57BL/6J male mice by periaortic elastase in combination with blocking elastin/collagen formation via 3-aminopropionitrile fumarate salt for 35 days. PDE5A protein levels detected by immunostaining were significantly reduced in mouse AAA. Sildenafil application in drinking water significantly aggravated aortic wall dilation and elastin degradation with pre-existing moderate AAA. The phosphorylation level of myosin light chain 2 at Ser19, a biochemical marker of SMC contraction, was significantly reduced by sildenafil in AAA. Proximity ligation assay further revealed that the interaction between cGMP and PKGI was significantly increased by sildenafil in AAA, suggesting an elevation of PKGI activation in AAA. Conclusions Sildenafil treatment aggravated the degradation of elastin fibers and progression of experimental AAA by dysregulating cGMP and contractile signaling in SMCs. Our findings may raise the caution of clinical usage of Viagra in aneurysmal patients.
Keyphrases
- aortic aneurysm
- smooth muscle
- protein kinase
- pulmonary hypertension
- pulmonary arterial hypertension
- abdominal aortic aneurysm
- drinking water
- nitric oxide
- aortic dissection
- pulmonary artery
- end stage renal disease
- binding protein
- endothelial cells
- ejection fraction
- single cell
- newly diagnosed
- gene expression
- oxidative stress
- chronic kidney disease
- poor prognosis
- peritoneal dialysis
- middle aged
- heart failure
- prognostic factors
- mesenchymal stem cells
- high glucose
- atrial fibrillation
- drug induced
- protein protein
- single molecule
- heavy metals
- risk assessment
- induced pluripotent stem cells
- electronic health record
- small molecule
- bone marrow
- adverse drug
- health risk assessment