Differential regulation of Akt, caspases and MAP kinases underlies smooth muscle cell apoptosis during aortic remodelling in SHR treated with amlodipine

Background and purpose: The regression of aortic hypertrophy is initiated by a transient wave of smooth muscle cell (SMC) apoptosis in spontaneously hypertensive rats (SHR) treated with antihypertensive drugs, although the molecular pathways remain unclear. Experimental approach: Enzymes involved in apoptosis regulation were examined daily during onset aortic remodelling in SHR treated with amlodipine (20 mg kg−1 day−1). Key results: Significant reduction of aortic SMC number occurred by day 3 of amlodipine, reaching -13% at 28 days, followed by a significant regression of medial hypertrophy by day 5, reaching -13% at 28 days. ISOL-positive (apoptotic) SMC nuclei increased by 4.6-fold between days 2 and 4, in temporal correlation with the activation of caspase-8 (2.7-fold) at day 2 only, caspase-3 at days 3 and 4 (1.7-fold) and caspase-9 at day 3 only (3.1-fold). Akt phosphorylation, a pro-survival pathway, was reduced prior to apoptosis at day 1 (-52%) and until day 3. During the first 6 days of amlodipine treatment, significant reduction in phosphorylation of mitogen-activated protein (MAP) kinases was transient for p38 (-46% at day 3 only) but continuous for ERK1/2 after 3 days (-40%), and for JNK after 4 days (>-50%). Conclusions and implications: Amlodipine inhibition of Akt occurred prior to and during SMC apoptosis induction, a process mediated by the early activation of caspase-8 followed by caspase-9 and -3 and associated with MAP kinase inhibition. These findings provide insights about the molecular pathways underlying SMC apoptosis leading to vascular remodelling during amlodipine treatment of hypertension. British Journal of Pharmacology (2007) 151, 1315–1323; doi:10.1038/sj.bjp.0707334