title: A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis.
abstract: To address the impact of antidiabetic drugs on cardiovascular safety is a matter of clinical concern. Preclinical studies revealed that various protective effects of dipeptidyl peptidase-4 inhibitor (DPP4i) on cardiovascular disease; however, its impact of on hypertension remains controversial.
  
  
  
  Teneligliptin (TEN; 10mg/kg/day/p.o.) ameliorates hypertension and cardiac remodeling by normalizing a rise of angiotensin-II (AngII) that specifically observed in spontaneously hypertensive rats (SHR). TEN had no effects on vasculature and concentrations of the DPP4-related vasoactive peptides (bradykinin, neuropeptide Y, and atrial natriuretic peptide). The primary action of TEN on BP lowering was due to restoring the AngII-induced manifestation of congestive heart failure observed in SHR. Sodium-proton pump exchanger type 1 (NHE-1) is a regulator of intracellular acidity (pHi) and implicated pathophysiological role in cardiac remodeling occurred in diseased myocardium. Cardiac NHE-1 expression level was increased in SHR and this was restored in TEN-treated SHR. AngII directly augmented cardiac NHE-1 expression and its activity that contributed to hypertrophic response. TEN attenuated the AngII-induced cardiac hypertrophy with decline in pHi via suppression of NHE-1. Loss of NHE-1 activity by specific inhibitor or RNA silencing promoted intracellular acidification and consistently attenuated the AngII-mediated cardiac hypertrophy.
  
  
  
  The present study revealed the protective actions of TEN on hypertension and comorbid cardiac remodeling via AngII/NHE-1 axis and the novel pathophysiological roles of intracellular acidification via NHE-1 in cardiac hypertrophy.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Haruya
authors.initials: H
authors.lastname: Kawase
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. Electronic address: ybando@med.nagoya-u.ac.jp.
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Aoyama
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Monji
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. Electronic address: murohara@med.nagoya-u.ac.jp.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011720:Pyrazoles; D017923:Sodium-Hydrogen Exchangers; D053778:Thiazolidines; C069139:growth factor-activatable Na-H exchanger NHE-1; D000804:Angiotensin II; D018819:Dipeptidyl Peptidase 4
keywords: Angiotensin-II; Cardiac remodeling; Dipeptidyl peptidase-4 inhibitor; Hypertension; Sodium-proton pump exchanger