Hypertension and cardiovascular injury: Chronic C-type natriuretic peptide treatments inhibits TGF-B1 signaling pathway and attenuates oxidative stress

CANIFFI, CAROLINA; GÓMEZ, MARTÍN; PRENTKI, ESTEFANÍA; ALCOBER, LUCÍA; ARRANZ, CRISTINA

CABA

Congreso; XXIII Congreso Argentino de Hipertensión Arterial; 2016

Sociedad Argentina de Hipertensión Arterial y International Society of Hypertension

C-type natriuretic peptide (CNP) has shown to attenuate fibrosis in hypertensive models and recentlyits second messenger cGMP has been associated with the inhibition of transforming growth factor beta (TGF-β) signalingpathway, one of the main signaling pathways involved in cardiovascular remodeling. Through activation of Smad2/3 and4 proteins, TGF-β1 can increase the synthesis of collagen type I and III, process also assited by inflammatory mediators.TGF-β1 also stimulates the expression of the catalytic subunit of NADPH oxidase and promotes the synthesis of variousextracellular matrix components by increasing the activity of this enzyme. Moreover, there is evidence that increasedreactive oxygen species can, in turn, stimulate the TGF-β1/Smad pathway.Therefore, the aim of this study was to determine if the TGF-β1 signaling pathway is involved in the attenuation of fibrosisin spontaneously hypertensive rats (SHR) treated with CNP and the effects in the oxidative state of these animals.Design and method: 12-week-old male SHR were infused with CNP (0.75 ug/hr) or saline (S) (osmotic pumps, 14 days).Systolic blood pressure (SBP, mmHg) was recorded by tail-cuff method. After treatment, animals were decapitated andthe thoracic aorta artery and left ventricle were extracted to determine: activity of NO synthase (NOS, pmol/g tissue.min),protein expression of endothelial NOS (eNOS, % relative to actin density) by Western blot, content of thiobarbituric acidreactive species (TBARS, nmol/mg protein) by fluorometry (excitation wavelength: 530 nm; emission wavelength: 550nm), TGF-β1 and Smad (% of staining area) by immunohistochemistry and collagen content (Sirius red staining, % ofstaining area). Statistical analysis : Student t test. n = 6 rats/group except TGF-β1LV and SmadLV: n = 4 rats/group.Results: Results are expressed as mean±SEM.SHR-S SHR-CNPSBP 186±4 159±5***NOSaorta 125±8 209±5***NOSLV 262±4 362±4***eNOSaorta 1.00±0.07 0.92±0.09eNOSLV 1.00±0.08 1.05±0.18TBARSaorta 0.37±0.02 0.27±0.02**TBARSLV 0.52±0.04 0.40±0.04TGF-β1aorta 25.1±0.7 18.5±0.6**TGF-β1LV 15.6±1.7 9.3±1.7*Smadaorta 6.07±0.74 2.75±0.44**SmadLV 17.3±3.4 12.3±2.0*Collagenaorta 34.0±2.0 18.9±3.0***CollagenLV 6.8±0.4 3.3±0.7*** p < 0.05 vs SHR-S; ** p < 0.01 vs SHR -S; *** p < 0.001 vs SHR -S.Conclusions: Our results show that CNP chronic treatment attenuates the expression of pro-fibrotic markers andoxidative stress in cardiovascular tissue, and contributes to the antifibrogenic effects of the natriuretic peptide in heartand aorta. Also, CNP enhances NO system and induces a drop in blood pressure. These beneficial effects of chronicadministration of CNP could be related to an overall improvement of target organ damage in this model of hypertension.