title: Apoptosis is not increased in myocardium overexpressing type 2 angiotensin II receptor in transgenic mice.
abstract: To determine whether angiotensin type 2 (AT(2)) receptor stimulation induces apoptosis in cardiomyocytes in vivo, we developed transgenic mice overexpressing the AT(2) receptor in a cardiac-specific manner, using the alpha-myosin heavy-chain promoter. Ten- to 12-week-old male homozygous transgenic mice (n=44) and wild-type mice (n=44) were used. Both transgenic and wild-type mice were given either saline (control), a subpressor dose of angiotensin II (100 ng. kg(-1). min(-1)), a pressor dose of angiotensin II (1000 ng. kg(-1). min(-1)) for 14 days, a pressor dose of angiotensin II for 28 days to investigate the effects of stimulation on both angiotensin type 1 (AT(1)) and AT(2) receptors, the AT(1) antagonist L158809 alone, or a combination of angiotensin II (1000 ng. kg(-1). min(-1)) and L158809 for 14 days to investigate the effects of selective AT(2) receptor stimulation. Apoptosis was analyzed in paraffin-embedded ventricular sections by the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) technique. In both transgenic and wild-type mice, administration of a subpressor dose of angiotensin II, L158809, or a combination of angiotensin II and L158809 did not significantly affect the tail-cuff blood pressure or heart-to-body weight ratio, whereas administration of a pressor dose of angiotensin II for 14 or 28 days significantly increased blood pressure and the heart-to-body weight ratio. However, there was no statistical difference between the effects of angiotensin II in transgenic and wild-type mice. The number of TUNEL-positive nuclei was approximately 0 to 10 per 100 000 cardiomyocytes, with no difference between transgenic and wild-type mice, regardless of saline infusion or any stimulation. In infarcted canine myocardial tissue sections for positive control, the number of TUNEL-positive nuclei was increased by 13.8 to 19.1 times compared with those in the noninfarcted myocardium. In conclusion, angiotensin II infusion for a period of 28 days failed to induce cardiomyocyte apoptosis regardless of the presence or absence of cardiac AT(2) receptor overexpression. It is unlikely that in mice the AT(2) receptor is a strong signal to induce cardiomyocyte apoptosis in vivo.
authors.affiliation: First Department of Internal Medicine, Hiroshima University Faculty of Medicine, Hiroshima, Japan. Hiroshi.Sugino@ma7.seikyou.ne.jp
authors.forename: H
authors.initials: H
authors.lastname: Sugino
authors.forename: R
authors.initials: R
authors.lastname: Ozono
authors.forename: S
authors.initials: S
authors.lastname: Kurisu
authors.forename: H
authors.initials: H
authors.lastname: Matsuura
authors.forename: M
authors.initials: M
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Oshima
authors.forename: M
authors.initials: M
authors.lastname: Kambe
authors.forename: Y
authors.initials: Y
authors.lastname: Teranishi
authors.forename: H
authors.initials: H
authors.lastname: Masaki
authors.forename: H
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D001835:Body Weight; D006339:Heart Rate; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D009929:Organ Size; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C070967:L 158809