Apoptosis in Target Organs of Hypertension

TLDR

Apoptosis, a programmed cell death process, often accompanies abnormalities in cell proliferation and differentiation. The study aimed to assess the extent of apoptosis in the heart, kidney, and brain of genetically hypertensive mice and rats, as well as in cultured vascular smooth muscle cells, during hypertrophy and remodeling. Apoptosis was identified by morphological changes, DNA fragmentation and laddering, and terminal deoxynucleotidyl transferase labeling of 3′‑OH DNA ends in extracted DNA and tissue sections. The study revealed increased apoptosis in the hearts of spontaneously hypertensive rats and in the hearts, kidneys, and brains of spontaneously hypertensive mice, with greater apoptotic induction in cultured aortic smooth muscle cells from SHR, and demonstrated that oligonucleosomal cleavage, but not large DNA fragmentation, was elevated in SHR vascular smooth muscle cells, underscoring dysregulated cell death as a novel pathogenic mechanism and therapeutic target in hypertension.

Abstract

Apoptosis or programmed cell death frequently parallels abnormalities in cell proliferation and differentiation. As hypertrophy/hyperplasia or remodeling occurs in organs affected by hypertension, we evaluated the degree of apoptosis in the heart, kidney, and brain in situ in genetically hypertensive mice and rats as well as in cultured vascular smooth muscle cells. Apoptosis was characterized by morphological features, DNA fragmentation, and laddering as well as by terminal deoxynucleotidyl transferase labeling of the 3' OH ends of both extracted DNA and tissue sections. The present report provides the first evidence of increased apoptosis in whole organs of genetically hypertensive rat and mouse strains: in the heart of spontaneously hypertensive rats (SHR) and in the heart (ventricular cardiomyocytes), kidney (inner cortex and medulla), and brain (cortex, striatum, hippocampus, and thalamus) of spontaneously hypertensive mice, with a higher effect of apoptotic inducers in cultured aortic smooth muscle cells derived from SHR. Both types of known apoptotic processes, oligonucleosomal cleavage and large DNA fragmentation, were observed in vascular smooth muscle cells, but only the former appeared to be increased in SHR. This study underlines the importance of cell death dysregulation in hypertension, reveals a new route for investigation of the pathogenesis of hypertension, and suggests novel targets of therapeutic intervention.