Eman Radwan1, Vishal Mali2, Samuel Haddox2, Amira El-Noweihi3, Manal Mandour3, Jun Ren4, Souad Belmadani2, Khalid Matrougui5. 1. Department of Physiological Sciences, EVMS, Norfolk, VA 23501, USA; Department of Medical Biochemistry, Assiut University, Egypt. 2. Department of Physiological Sciences, EVMS, Norfolk, VA 23501, USA. 3. Department of Medical Biochemistry, Assiut University, Egypt. 4. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. 5. Department of Physiological Sciences, EVMS, Norfolk, VA 23501, USA. Electronic address: matrouk@evms.edu.
Abstract
BACKGROUND: Microvascular dysfunction is a major complication in hypertensive patients. We previously reported that CD4+CD25+ T regulatory cells (Treg) play an important preventive role in hypertension-induced vascular dysfunction. However, whether Treg cells therapy and autophagy inhibition could rescue Treg cells survival and microvascular function in established hypertension is an important question that remained unanswered. METHODS & RESULTS: Here we showed that Treg cells from mice model of established hypertension displayed an enhanced apoptotic rate, which was rescued with Treg cells transfer and autophagy inhibition. We also showed increased autophagy in mesenteric resistance artery (MRA) in mice with established hypertension. Importantly, the inhibition of autophagy or one single transfer of Treg cells into mice with established hypertension improved the microvascular function independently of high blood pressure. The protection involves the modulation of interleukin-10 (IL-10), inflammation, endoplasmic reticulum (ER) stress, oxidative stress, Akt, and eNOS. CONCLUSIONS: The present study suggests that Treg cells survival is regulated by autophagy. Also, Treg cells as a cellular therapy aimed at rescuing the microvascular function through an autophagy-dependent mechanism and independently of arterial blood pressure lowering effects. Because our mouse model of established hypertension mimics the clinical situation, our results have the potential for new therapeutic approaches that involve the manipulation of Treg cells and autophagy to overcome established hypertension-induced cardiovascular complications.
BACKGROUND:Microvascular dysfunction is a major complication in hypertensivepatients. We previously reported that CD4+CD25+ T regulatory cells (Treg) play an important preventive role in hypertension-induced vascular dysfunction. However, whether Treg cells therapy and autophagy inhibition could rescue Treg cells survival and microvascular function in established hypertension is an important question that remained unanswered. METHODS & RESULTS: Here we showed that Treg cells from mice model of established hypertension displayed an enhanced apoptotic rate, which was rescued with Treg cells transfer and autophagy inhibition. We also showed increased autophagy in mesenteric resistance artery (MRA) in mice with established hypertension. Importantly, the inhibition of autophagy or one single transfer of Treg cells into mice with established hypertension improved the microvascular function independently of high blood pressure. The protection involves the modulation of interleukin-10 (IL-10), inflammation, endoplasmic reticulum (ER) stress, oxidative stress, Akt, and eNOS. CONCLUSIONS: The present study suggests that Treg cells survival is regulated by autophagy. Also, Treg cells as a cellular therapy aimed at rescuing the microvascular function through an autophagy-dependent mechanism and independently of arterial blood pressure lowering effects. Because our mouse model of established hypertension mimics the clinical situation, our results have the potential for new therapeutic approaches that involve the manipulation of Treg cells and autophagy to overcome established hypertension-induced cardiovascular complications.
Authors: Amrita V Pai; Crystal A West; Aline M Arlindo de Souza; Parnika S Kadam; Emma J Pollner; David A West; Jia Li; Hong Ji; Xie Wu; Michelle J Zhu; Chris Baylis; Kathryn Sandberg Journal: Am J Physiol Renal Physiol Date: 2019-06-26