FAK, RhoA and p38MAPK modulates apoptosis mediated by Ang II AT 2 receptors

MANZUR, MARIA JIMENA; AGUILERA, MILTON OSMAR; KOTLER, MONICA; BERÓN, WALTER; CIUFFO, GLADYS

JOURNAL OF CELLULAR BIOCHEMISTRY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2018

0730-2312

Apoptosis plays an important role in cellular processes such as development, differentiation and homeostasis. Although it is well-accepted the participation of Ang II AT2 receptors in cellular apoptosis, the signaling pathway involved in thisprocess is not well established. We evaluated the participation of signaling proteins FAK, RhoA and p38MAPK in apoptosis induced by Angiotensin II via AT2 receptors overexpressed in HeLa cells. Following a short stimulation time(120-240 min) with Ang II, HeLa-AT2 cells showed nuclear condensation, stress fibers disassembly and membrane blebbing. Focal adhesion kinase (FAK), classically involved in cytoskeleton reorganization, has been postulated as anearly marker of cellular apoptosis. Thus, we evaluated FAK cleavage, detected at early stimulation times (15-30 min). Apoptosis was confirmed by increased caspase 3 cleavage and enzymatic activity of caspase-3/7. Participation ofRhoA was evaluated. HeLa-AT2 cells over-expressing RhoA wild-type (WT) or their mutants, RhoA V14 (constitutively active form) or RhoA N19 (dominant negative form) were used to explore RhoA participation. HeLa-AT2 cells expressing the constitutively active variant RhoAV14 showed enhanced apoptotic features at earlier times as compared to cells expressing the WT variant. RhoA N19 expression prevented nuclear condensation /caspase activation. Inhibition of p38MAPK caused an increase in nuclear condensation and caspase 3/7 activation, suggesting a protective role of p38MAPK. Our results clearly demonstrated that stimulation of AT2 receptors induce apoptosis with participation of FAK and RhoA while p38MAPK seems to play a pro-survival role.