Nebivolol Induces Distinct Changes in Profibrosis MicroRNA Expression Compared With Atenolol, in Salt-Sensitive Hypertensive Rats

Abstract

In a pilot study, 6-week-old Dahl salt-sensitive (SS/JrHsdMcwiCrl) rats were treated with Teklad LM-485 low-salt (LS, 0.3% NaCl) or AIN-76A high-salt (HS, 8% NaCl) diet. After 4 weeks, at age 10 weeks, rats were randomized to (1) LS+vehicle, (2) HS+vehicle, (3) HS+NEB (10 or 20 mg/kg per day, and (4) HS+atenolol (ATN; 25 or 50 mg/kg per day). Drugs were delivered via osmotic pumps with 3 animals per group. Heart rate (HR) and systolic blood pressure (SBP) were measured using a tail cuff monitor (ADInstruments, Monrovia) once a week until age of 18 weeks. Animals were trained for the SBP measurements 3× a week for 2 weeks before the beginning of the protocol. On the basis of the pilot results, we continued with the dose of NEB 20 mg/kg per day and ATN 50 mg/kg per day because these doses achieved similar effects on SBP and HR. In an additional experiment, 6-week-old Dahl SS rats were treated with LS or HS diet. After 4 weeks, at age 10 weeks, rats were randomized Abstract-Nebivolol is a selective β1-blocker with nitric oxide-enhancing effects. MicroRNAs are small noncoding RNA molecules that downregulate gene expression. We compared the effects of nebivolol and atenolol, a first generation β1-selective blocker, on left ventricular hypertrophy, fibrosis, and function and microRNA expression in a rodent model of hypertension. Dahl salt-sensitive rats received either low-salt chow (control) or AIN-76A high-salt (8% NaCl) diet and randomized to vehicle (high-salt), nebivolol (20 mg/kg per day), or atenolol (50 mg/kg per day) for 8 weeks. High-salt induced left ventricular hypertrophy and fibrosis and decreased the expression of miR-27a, -29a, and -133a. Nebovolol attenuated deterioration of left ventricular systolic function, remodeling, and fibrosis more than atenolol, despite similar effects on heart rate and blood pressure. Nebivolol, but not atenolol, prevented the decrease in miR-27a and -29a induced by high-salt. Nebivolol and atenolol equally attenuated the decrease in miR-133a. In vitro overexpression of miR27a, -29a, and -133a inhibited cardiomyocyte hypertrophy and reduced collagen expression. Both miR-27a and -29a target Sp1, and miR-133a targets Cdc42. Pharmacological inhibition of Sp1 and Cdc42 decreased myocardial fibrosis and hypertrophy. Our data support a differential microRNAs expression profile in salt-induced hypertension. Nebivolol substantially attenuated cardiac remodeling, hypertrophy, and fibrosis more than atenolol. These effects are related to attenuation of the hypertension-induced decrease in miR-27a and -29a (with a subsequent decrease in Sp1 expression) and miR-133a (with a subsequent decrease in Cdc42

The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist

“…2′,3′-cAMP is generally formed from the breakdown of the poly-A tails on mRNA and is found in abundance in apoptotic cells [39]; therefore, nebivolol did not trigger the degradation of mRNA and is likely not toxic in MEFs. The constellation of nucleosides that were increased suggests that there is increased translation and transcription, which fits with previous studies indicating that nebivolol increases dimethylarginine dimethylaminohydrolase transcript and protein levels [40] and that it alters microRNA expression [41]. Adenosine did not increase, which appears to contradict the translation and transcription hypothesis, yet this may be due to a portion of the increased inosine originating from adenosine degradation.…”

“…This explains how a β-blocker that is highly specific for the β 1 -AR results in activating signaling pathways without invoking the need for a second receptor. However, it remains an open question if this explains the unique in vivo effects attributed to nebivolol [41], [45]. Further studies will have to be conducted to answer this question fully; however, these data present a plausible explanation for nebivolol-mediated signaling, specifically in the endothelium.…”

Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells

“…Preference was given to those miRNAs showing altered expression due to β-blocking agents observed in other systems6747484950. The relative expression of these miRNAs was quantified by realtime q-PCR.…”

Non-coding RNAs and Hypertension–Unveiling Unexpected Mechanisms of Hypertension by the Dark Matter of the Genome

“…Nebivolol, a β1 blocker andβ3 activator, may prevent arterial dysfunction and remodeling by inhibiting miR-320 that targets insulin growth factor-1 receptor (IGR1R), and by overexpressing miR-26b and 
miR-21 that target phosphatase and tensin homolog on chromosome ten (PTEN) in Dahl Salt Sensitive (DSS) hypertensive rat model [103]. As mentioned above, nebivolol has also been reported to attenuate cardiac remodeling, hypertrophy and fibrosis through inducing miR-27a, -29a targeting Sp1 and miR–133a targeting Cdc42 in DSS hypertensive rat model [47]. The role of PTEN as a target of miR-21 in arterial remodeling is depicted in other reports (miR-143-FRA-1-miR-21 axis) [102].…”