Biochemistry in medicine: hypertension minireview series.

Hypertension, or high blood pressure, is a serious health problem worldwide and is operationally defined as a resting systolic/diastolic blood pressure greater than 140/90 mm Hg. The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recently issued guidelines defining people with systolic blood pressures between 120 and 139 mm Hg and diastolic pressures between 80 and 89 mm Hg as “pre-hypertensive.” Those who fall into this category are more likely to develop frank hypertension and thus require active clinical intervention. Nearly one-quarter of the world's adult population is hypertensive! More than 75 million people in the United States alone are hypertensive, and an additional 50 million lie in the pre-hypertensive range. Most often, hypertension displays no overt symptomatology, hence the moniker “the silent killer.” In many, if not most, cases, the underlying etiology of the disease is unknown (essential hypertension). To complicate matters more, hypertension is a multifactorial disease, rarely resulting from a single identifiable cause or single gene mutation. Many factors influence blood pressure: whole-body salt and volume load, autonomic nervous system output, lipid and cholesterol metabolism, kidney disease, medications, and lifestyle activities, such as smoking, drinking, and exercise (or lack thereof). There is a multitude of genetic influences as well; some candidate high blood pressure genes include 11-β-hydroxysteroid dehydrogenases B1 and B2; apolipoproteins A1, A2, and C2-C4; chloride-bicarbonate exchangers 1, 2, and 3; endothelin-1, -2, and -3; and vascular endothelial growth factors A, B, and C, just to mention a few. (At present, more than 150 genes are listed as potentially contributory to hypertension.) There is a plethora of sequelae that result from uncontrolled hypertension, and none of them is good: cardiovascular problems (e.g. heart failure), cerebral vascular problems (e.g. stroke), and renal problems (e.g. end-stage renal disease requiring dialysis and, ultimately, transplantation). Many biochemical processes are affected by hypertension; abnormalities or dysregulation of many biochemical pathways can contribute to the development of hypertension. This thematic minireview series will explore several novel aspects of the biochemistry of hypertension and how this biochemistry interfaces at the physiological and clinical levels. The first minireview, by Joseph A. Hill of the Division of Cardiology, Department of Medicine, University of Texas Southwestern Medical Center, explores the role of cardiac cell autophagy in hypertension. The mechanisms of autophagy as related to hypertension-induced cardiac remodeling, ultimately contributing to ischemic heart disease and failure, will be examined. In the second minireview, Curt D. Sigmund, a professor of medicine and molecular physiology and biophysics at the University of Iowa and Director of the Center on the Functional Genomics of Hypertension at the university's Carver College of Medicine, summarizes the role that the peroxisome proliferator-activated receptor γ transcription factor plays in the endothelium and vascular smooth muscle cells using genetically altered mouse models of hypertension. The third minireview in this series is by Rebecca P. Hughey and Thomas R. Kleyman, both of the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine. They examine the central position that a specific ion channel, namely ENaC (or the epithelial Na channel) has in Liddle disease. This autosomal recessive genetic disease produces severe hypertension and is caused by gain-of-function mutations within the genes encoding the C-terminal regions of the β- and/or γ-subunits of this renal distal tubular collecting duct-located ion channel. James K. Bubien, associate professor of physiology and biophysics at the University of Alabama at Birmingham, continues this theme in the fourth minireview by summarizing evidence that the hormonal stimulation of ENaC by aldosterone and insulin, two hormones elevated in obese individuals with therapy-resistant hypertension, may contribute to the hypertension that accompanies obesity. He also proposes a different paradigm in which the serum potassium level plays an important, if not critical, role in hypertension. The fifth and final minireview of this series is by John E. Hall, Associate Vice Chancellor for research at the University of Mississippi Medical Center and Editor-in-Chief of the journal Hypertension. The focus of his article is also obesity and hypertension. He discusses the obesity-induced activation of the sympathetic nervous system by the leptin-melanocortin 4 receptor pathway. Thus, this minireview series explores several major biochemical axes that, when gone awry, contribute to the development of or are a consequence of hypertension. These include the sympathetic nervous system, the vascular and cardiac systems, and critical transport systems in the kidney. It is the overall goal of this thematic minireview series to link biochemical processes to the understanding of the important clinical problem of hypertension. By emphasizing a strong connection between laboratory research and clinical medicine, we hope to stimulate interest in this specific translational topic among biochemists, clinicians, and graduate and medical students. It is also hoped that an appreciation of the biochemical underpinnings of this disease will be realized and that clarity and a strong rationale for why basic biochemical research is so important will ensue.