Common Genetic Mechanisms of Blood Pressure Elevation in Two Independent Rodent Models of Human Essential Hypertension

Abstract

Genetic studies of essential hypertension, a complex, polygenic, and age-dependent disorder, have not been able to completely elucidate the genes responsible for development of the trait. We used a novel strategy to compare gene expression in the adrenal gland of two independent rodent models of human essential hypertension (the spontaneously hypertensive rat, SHR, and the blood pressure high mouse, BPH), with the goal of uncovering shared, common genetic mechanisms of hypertension across mammalian species that might, therefore, be pertinent to human hypertension. We deliberately studied young, 4- to 5-week-old, "prehypertensive" SHR and BPH that had not yet developed complete elevations in blood pressure (BP), so that we could minimize the impact of chronic, sustained BP elevation, age, and other confounding factors on gene expression, therefore increasing the likelihood that differential expression reflects relatively early pathogenic mechanisms in hypertension, rather than later responses to, or compensations for BP elevation. We compared transcript expression patterns of genes orthologous between the rat and the mouse, and presented candidate genes for hypertension that are differentially expressed in the same direction in SHR and BPH (ie, overexpressed in both SHR and BPH, or underexpressed in both SHR and BPH). Then we used a systems biology approach to analyze expression patterns in biochemical pathways and networks to isolate systems involved in hypertension pathology in both SHR and BPH. We found transcript pattern evidence for involvement of several systems in the pathology of hypertension in SHR and BPH: adrenal catecholamines and sympathetic function; steroid hormone synthesis, catabolism, and its contribution to enhanced glucocorticoid sensitivity in SHR; oxidative stress and its role as a common mechanism of vascular and end-organ injury; and intermediary metabolism with global but mechanistically different perturbations in SHR and BPH. Approximately 10% of the differentially expressed orthologous genes we studied shared a common direction of expression in the two hypertensive rodent strains, suggesting fundamental transcriptional mechanisms in common whereby mammals can elevate BP or respond to such elevation; even these shared orthologs spanned a diverse set of biological processes, reinforcing the multifactorial and complex nature of hypertension.

Does Telomere Shortening Precede the Onset of Hypertension in Spontaneously Hypertensive Mice?

“…The BPH/2J strain parallels human hypertension, with increased blood pressure, heart rate, endothelial dysfunction, and reduced survival, compared to the normotensive BPN/3J control strain (Schlager & Sides, 1997). The BPH/2J mice are pre-hypertensive at 4 weeks (Friese et al, 2005) and have been shown to exhibit increased blood pressure at 7 weeks of age, when compared to the normotensive controls (BPN/3J) (Schlager & Sides, 1997). We have previously shown that at 12 weeks of age, systolic blood pressure is on average 34 mmHg higher in BPH/2J male mice, compared with BPN/3J mice of the same age (Chiu et al, 2014).…”

Molecular mechanism of interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

“…It is generated from chromogranin A (CHGA) (Biswas et al, 2009;Helle, 2010), a major protein costored and co-released with catecholamines from secretory granules of chromaffin cells and adrenergic neurons (Sahu et al, 2010;Taupenot et al, 2003). Although CHGA is overexpressed in genetic hypertension (Friese et al, 2005;O'Connor et al, 1999;Takiyyuddin et al, 1995), the plasma CST level is diminished not only in established hypertensive patients but also in their normotensive offspring . Infusion of CST into dorsal hand veins triggers dose-dependent vasodilation in human subjects (Fung et al, 2010).…”

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

“…BHR are the offspring of female spontaneously hypertensive rats (SHR) and normotensive male WKY rats (51). SHR exhibit exaggerated cardiovascular responses to acute stress and develop glucocorticoiddependent hypertension (20,41,50). BHR also have enhanced stress reactivity and are susceptible to stress-induced hypertension (21,51).…”