Abstrakt
Several models of essential hypertension have revealed abnormalities in pathways regulating cell proliferation and programmed cell death (apoptosis). The increased proliferative phenotype found as early as birth in hypertensives is accompanied by age-dependent alterations in apoptosis, contributing to neonatal hyperplasia of the heart, aorta, and kidneys.
During the course of life, accelerated cell turnover occurs and is modifiable by antihypertensive therapy, notably by inhibitors of the renin-angiotensin system. We consider the hypothesis that hypertension may be a case of accelerated aging.
Part of this process may involve the defective regulation of cell proliferation in cardiovascular target organs via a putative specific senescence pathway. Candidates include abnormalities in cell cycle control genes, the renin-angiotensin pathway, and regulation of the telomerase pathway.
Abnormal activity of angiotensin II-regulated Na+ transporters and augmented production of endogenous ouabain-like substances have been detected in experimental models of primary hypertension. Recent data show that both ouabain and intracellular Na+ are involved in the regulation of gene expression and apoptosis.
The relevance of neonatal and early life development as a predictor of cardiovascular disease outcomes later in life is an intriguing issue that remains to be better defined. In this regard, understanding the complex genetic and epigenetic influences contributing to aging and age-related diseases will be a major goal.
Because phenotype development can be analyzed longitudinally during the course of life in recombinant inbred rat strains, these models will allow a systematic approach to the molecular analysis of senescence pathway regulation, their determinants early in life, and their control by hereditary and epigenetic factors, including pharmacotherapy.