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Pharmacological inhibition of mTOR attenuates DOCA-salt-induced hypertension and related pathophysiology: regulation of oxidative stress, inflammation and cardiovascular hypertrophy in male rats.
Journal of Cardiovascular Pharmacology  (IF3.105),  Pub Date : 2021-11-23, DOI: 10.1097/fjc.0000000000001187
Meryem Temiz-Resitoglu, Demet Sinem Guden, Sefika Pinar Senol, Ozden Vezir, Nehir Sucu, Deniz Kibar, Sakir Necat Yılmaz, Bahar Tunctan, Kafait U Malik, Seyhan Sahan-Firat

The present study aimed to explore the contribution of mTOR in deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA-salt loading resulted in an increase in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) along with the activity of ribosomal protein S6 (rpS6), the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the 4th week of DOCA-salt administration normalized the SBP and attenuated rpS6 activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, oxidative stress, and infiltration of macrophages (CD68+), the marker of inflammation, were also reduced in rapamycin-treated DOCA-salt hypertensive rats. In addition, renal hypertrophy and dysfunction were also reduced with rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in the heart, aorta, and kidney were minimized by rapamycin. These data indicate that mTOR plays an important role in regulating blood pressure and the development of cardiovascular and renal pathophysiological changes, most likely due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with macrophages infiltration in the heart, kidney, and aorta. Pharmacological inhibition of mTOR and related signaling pathways could serve as a novel target for the treatment of hypertension.