Abstract
MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are emerging as key regulators in cardiovascular development and disease. MiRNAs are involved in cardiac hypertrophy, heart failure and remodeling following cardiac infarction; however, miRNAs involved in hypertension have not been thoroughly investigated. We have recently reported that specific miRNAs play an integral role in Angiotensin II receptor (AT1R) signaling, especially after activation of the Gαq signaling pathway. Since AT1R blockers are widely used to treat hypertension, we undertook a detailed analysis of potential miRNAs involved in Angiotensin II (AngII) mediated hypertension in rats and hypertensive patients, using miRNA microarray and qPCR analysis. The miR-132 and miR-212 are highly increased in the heart, aortic wall and kidney of rats with hypertension (159 ± 12 mm Hg) and cardiac hypertrophy following chronic AngII infusion. In addition, activation of the endothelin receptor, another Gαq coupled receptor, also increased miR-132 and miR-212. We sought to extend these observations using human samples by reasoning that AT1R blockers may decrease miR-132 and miR-212. We analyzed tissue samples of mammary artery obtained from surplus arterial tissue after coronary bypass operations. Indeed, we found a decrease in expression levels of miR-132 and miR-212 in human arteries from bypass-operated patients treated with AT1R blockers, whereas treatment with β-blockers had no effect. Taken together, these data suggest that miR-132 and miR-212 are involved in AngII induced hypertension, providing a new perspective in hypertensive disease mechanisms.
Highlights
Persistent elevation of systemic blood pressure is one of the most prevalent medical conditions involving the cardiovascular system and affects as many as one billion people worldwide [1]
Infusion of Angiotensin II (AngII) for 10 days resulted in a stable and significant elevation in blood pressure to 159 ± 12 mm Hg (p < 0.001, n = 7) at day 10, as compared to control rats that remained constant at 98 ± 4 mm Hg (n = 8) (Figure 1A)
We found that short time (4 h) AngII infusion resulted in an acute and significant 29 mm Hg increase in blood pressure (p < 0.001, n = 6) (Figure 1B)
Summary
Persistent elevation of systemic blood pressure (hypertension) is one of the most prevalent medical conditions involving the cardiovascular system and affects as many as one billion people worldwide [1]. Angiotensin II (AngII) controls blood pressure and fluid homeostasis through its receptors, AT1R and AT2R, and through stimulation of aldosterone [1]. AngII receptors are expressed in tissues that have an impact on blood pressure control, including heart, kidney and vasculature [3,4]. The classical AngII responses in the cardiovascular and renal systems are mediated mainly by AT1R signaling [3,4,5], including heterotrimeric G-protein activation and downstream signaling through the canonical MAP kinases ERK1/2, which, in turn, regulate gene transcription [4]. Specific inhibitors of AngII pathways, including AT1R blockers, dramatically lower blood pressure in hypertensive patients and slow the progression of cardiovascular disease [1,3]
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