Angiotensin II, mitochondria, cytoskeletal, and extracellular matrix connections: an integrating viewpoint

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 296; no. 3; pp. H550 - H558
• Main Authors: de Cavanagh, Elena MV, Ferder, Marcelo, Inserra, Felipe, Ferder, Leon
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2009
• Subjects: ACE inhibitors; Adenosine triphosphatase; Angiotensin II - metabolism; Animals; Cardiovascular disease; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Cardiovascular system; Cells; Cytoskeleton; Cytoskeleton - metabolism; Energy Metabolism; Extracellular Matrix - metabolism; Focal Adhesions - metabolism; Humans; Integrins - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Size; Receptor, Angiotensin, Type 1 - metabolism; Signal Transduction; Transforming Growth Factor beta1 - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01176.2008

1 Institute of Cardiovascular Pathophysiology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina; 2 Fresenius Medical Care Argentina, Buenos Aires, Argentina; and 3 Department of Physiology and Pharmacology, Ponce School of Medicine, Ponce, Puerto Rico Submitted 11 November 2008 ; accepted in final form 14 January 2009 ABSTRACT Malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage associated with hypertension and other disease conditions. Eukaryotic cells move, assume their shape, resist mechanical stress, accommodate their internal constituents, and transmit signals by relying on the constant remodeling of cytoskeleton filaments. Mitochondrial ATP is needed to support cytoskeletal dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal motility, morphology, localization, and function. Extracellular matrix (ECM) quantity and quality influence cellular growth, differentiation, morphology, survival, and mobility. Mitochondria can sense ECM composition changes, and changes in mitochondrial functioning modify the ECM. Maladaptive ECM and cytoskeletal alterations occur in a number of cardiac conditions and in most types of glomerulosclerosis, leading to cardiovascular and renal fibrosis, respectively. Angiotensin II (ANG II), a vasoactive peptide and growth factor, stimulates cytosolic and mitochondrial oxidant production, eventually leading to mitochondrial dysfunction. Also, by inducing integrin/focal adhesion changes, ANG II regulates ECM and cytoskeletal composition and organization and, accordingly, contributes to the pathogenesis of cardiovascular remodeling. ANG II-initiated integrin signaling results in the release of transforming growth factor-β 1 (TGF-β 1 ), a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by ANG II is preceded by ANG II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. ANG II-dependent TGF-β 1 release is a potential link between ANG II, ECM, and cytoskeleton derangements and mitochondrial dysfunction. It is necessary to emphasize that the present hypothesis is among many other plausible explanations for ANG II-mediated mitochondrial dysfunction. A potential limitation of this proposal is that the results compiled here were obtained in different cells, tissues, and/or experimental models. cytoskeleton; transforming growth factor-β; integrin; renin-angiotensin system Address for reprint requests and other correspondence: L. Ferder, Dept. of Physiology and Pharmacology, Ponce School of Medicine, PO Box 7004, Ponce, Puerto Rico, 00732-7004 (e-mail: leferder{at}psm.edu )