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(Circulation. 2004;109:2227-2233.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Regulation of Proangiogenic Factor CCN1 in Cardiac Muscle

Impact of Ischemia, Pressure Overload, and Neurohumoral Activation

Denise Hilfiker-Kleiner, PhD^*; Karol Kaminski, MD^*; Agnieszka Kaminska, MSc; Martin Fuchs, MD; Gunnar Klein, MD; Edith Podewski, MD; Karsten Grote, PhD; Ioulia Kiian, PhD; Kai C. Wollert, MD; Andres Hilfiker, PhD; Helmut Drexler, MD

From the Departments of Cardiology and Angiology (D.H.-K., A.K., M.F., G.K., E.P., K.G., K.C.W., A.H., H.D.) and Nephrology (I.K.), Hannover Medical School, Hannover, Germany; and Department of Cardiology, Bialystok Medical School, Bialystok, Poland (K.K.).

Correspondence to Helmut Drexler, MD, Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail Drexler.Helmut{at}MH-Hannover.de

Received April 3, 2003; de novo received November 27, 2003; revision received February 3, 2004; accepted February 5, 2004.

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.

Methods and Results— Ang II, signaling via the angiotensin type 1 (AT₁) receptor, and ₁-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 ₁-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.

Key Words: angiogenesis • myocardial infarction • ischemia • pressure • signal transduction

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