Regulation of proangiogenic factor CCN1 in cardiac muscle: impact of ischemia, pressure overload, and neurohumoral activation.
BACKGROUND
CCN1, a potent proangiogenic factor, is induced in the vasculature by tissue injury, angiotensin II (Ang II), and growth factor stimulation. Because these conditions occur in myocardial ischemia and pressure overload, we investigated the regulation of CCN1 in cardiomyocytes in vitro and in the heart in vivo.


RESULTS
Ang II, signaling via the angiotensin type 1 (AT1) receptor, and alpha1-adrenergic stimulation with phenylephrine induced CCN1 expression in ventricular cardiomyocytes isolated from 1- to 3-day-old rats. Cell culture supernatant of Ang II-treated cardiomyocytes induced migration of smooth muscle cells, which was abolished by neutralizing antibody to CCN1. Ang II- and phenylephrine-mediated induction of CCN1 expression in cardiomyocytes was completely abolished by inhibition of MEK/extracellular signal-regulated kinases (ERK) or protein kinase C (PKC). Likewise, mechanical stretch induced CCN1 expression in cardiomyocytes, an effect that was prevented by AT1 receptor blockade or PKC inhibition. Similarly, pressure overload in vivo upregulated myocardial CCN1 expression levels via AT1 receptor- and PKC-dependent mechanisms. After myocardial infarction in mice, CCN1 expression was strongly induced in both ischemic and remote left ventricular myocardium. Marked CCN1 protein expression was noted in cardiomyocytes of patients with end-stage ischemic cardiomyopathy but was almost absent in nonfailing human myocardium.


CONCLUSIONS
Pressure overload, ischemia, and neurohormonal factors, such as Ang II or alpha1-adrenergic stimuli, induce myocardial expression of CCN1, a potent proangiogenic factor, supporting the notion that CCN1 may play an important role in the adaptation of the heart to cardiovascular stress.
Hilfiker-Kleiner
Denise
D
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Kaminski
Karol
K
Kaminska
Agnieszka
A
Fuchs
Martin
M
Klein
Gunnar
G
Podewski
Edith
E
Grote
Karsten
K
Kiian
Ioulia
I
Wollert
Kai C
KC
Hilfiker
Andres
A
Drexler
Helmut
H
D000470:Alkaloids; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D053119:Benzophenanthridines; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D055515:Cysteine-Rich Protein 61; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D019899:Paracrine Communication; D010617:Phenanthridines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology; D013314:Stress, Mechanical; D000077333:Telmisartan; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000470:Alkaloids; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D053119:Benzophenanthridines; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; C501849:CCN1 protein, rat; D055515:Cysteine-Rich Protein 61; D005419:Flavonoids; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009281:Naphthalenes; D010617:Phenanthridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C061465:calphostin complex; D000804:Angiotensin II; D010656:Phenylephrine; C016299:chelerythrine; D011493:Protein Kinase C; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077333:Telmisartan; D009638:Norepinephrine