Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy.
Angiotensin II (Ang II) has a significant role in regulating cardiac homeostasis through humoral, autocrine and paracrine pathways, via binding to the plasma membrane AT1 receptor. Recent literature has provided evidence for intracrine growth effects of Ang II in some cell lines, which does not involve interaction with the plasma membrane receptor. We hypothesized that such intracrine mechanisms are operative in the heart and likely participate in the cardiac hypertrophy induced by Ang II. Adenoviral and plasmid vectors were constructed to express Ang II peptide intracellularly. Neonatal rat ventricular myocytes (NRVMs) infected with the adenoviral vector showed significant hypertrophic growth as determined by cell size, protein synthesis and enhanced cytoskeletal arrangement. Adult mice injected with the plasmid vector developed significant cardiac hypertrophy after 48 h, without an increase in blood pressure or plasma Ang II levels. This was accompanied by increased transcription of transforming growth factor-beta (TGF-beta) and insulin-like growth factor-1 (IGF-1) genes. Losartan did not block the growth effects, excluding the involvement of extracellular Ang II and the plasma membrane AT1 receptor. These data demonstrate a previously unknown growth mechanism of Ang II in the heart, which should be considered when designing therapeutic strategies to block Ang II actions.
Baker
Kenneth M
KM
Division of Molecular Cardiology, Cardiovascular Research Institute, The Texas A&M University System Health Science Center, College of Medicine, 1901 S 1st Street, Building 205, Temple 76504, USA.
Chernin
Mitchell I
MI
Schreiber
Taylor
T
Sanghi
Sandhya
S
Haiderzaidi
Seema
S
Booz
George W
GW
Dostal
David E
DE
Kumar
Rajesh
R
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005786:Gene Expression Regulation / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D017931:DNA Primers; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D019808:Losartan