D Duguay1, D deBlois. 1. Department of Pharmacology, University of Montreal, 2900 Edouard-Montpetit, Montreal, Quebec, Canada.
Abstract
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.
BACKGROUND AND PURPOSE: The regression of aortic hypertrophy is initiated by a transient wave of smooth muscle cell (SMC) apoptosis in spontaneously hypertensiverats (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.