[Frontiers in Bioscience 14, 2307-2334, January 1, 2009]

Integrins and proximal signaling mechanisms in cardiovascular disease

Hind Lal1, Suresh K. Verma1, Donald M. Foster2, Honey B. Golden1, John C. Reneau1, Linley E. Watson3, Hitesh Singh4, David E. Dostal1

1Division of Molecular Cardiology, Cardiovascular Research Institute, The Texas AandM University System Health Science Center, College of Medicine, Scott and White, 2Central Texas Veterans Health Care System, Temple, Texas 76504; 3Division of Cardiology, 4Internal Medicine, Scott and White Memorial Hospital, Temple TX 76508

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Integrin structure and function
2.2. Integrin expression in the cardiovascular system
2.2.1. Cardiac myocytes
2.2.2. Cardiac fibroblasts
3. Integrin bidirectional signaling across the plasma membrane
3.1. Mechanical load and integrin activation
3.2.Lipid microdomains
3.2.1. Lipid rafts
3.2.2. Caveole
3.3. Actin-Integrin adhesion complexes
3.3.1. Focal complexes
3.3.2. Focal adhesions
3.3.3. Fibrillary adhesions
3.4. Focal adhesion kinase
3.4.1. Structure and activation
3.4.2. Expression and regulation
3.4.3. Role of FAK in vascular function
3.4.4. Role of FAK in cardiac function
3.5. Integrin-Linked Kinase
3.5.1. Structure and function
3.6. Integrin-mediated Akt activation
3.7. Rho Family of GTPases
3.7.1. Actin-dependent signaling of Rho GTPases
3.7.2. Actin-independent signaling by Rho GTPases
3.7.3. RhoA and Rac1 in cardiovascular signaling
3.8. Mitogen-activated protein kinases (MAP kinases)
3.8.1. Integrin-induced ERK activation
3.8.2. Integrin-mediated p38 and JNK activation
4. Cross-talk with other receptor systems
5. Therapeutic targeting of integrin signaling
5.1. ILK as a Therapeutic Target
5.2. MAP kinases as therapeutic targets
5.2.1. p38 inhibitors
5.2.2. JNK inhibitors
5.3. Rho GTPases as therapeutic targets
5.3.1. Rho-kinase (ROCK) inhibitors
5.3.2. Statins
6. Summary and perspectives
7. Acknowledgement
8. References

1. ABSTRACT

Integrins are heterodimeric cell-surface molecules, which act as the principle mediators of molecular dialog between a cell and its extracellular matrix environment. In addition to their structural functions, integrins mediate signaling from the extracellular space into the cell through integrin-associated signaling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein-2). Via these molecules, integrin signaling tightly and cooperatively interacts with receptor tyrosine kinases (RTKs) signaling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In the heart and blood vessels, the function and regulation of these molecules can be partially disturbed and thus contribute to cardiovascular diseases such as cardiac hypertrophy and atherosclerosis. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these systems (1).