Cytoskeletal Mechanics in Pressure-Overload Cardiac Hypertrophy

Abstract

We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on the cardiocyte contractile apparatus in pressure-overload cardiac hypertrophy.

Tensegrity-based mechanosensing from macro to micro

“…For example, the finding that microtubules bear compression in living cells is extremely relevant for heart physiology because an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton caused by pressure overload can physically interfere with inward-directed shortening of the myofibrillar bundle, and hence lead to contractile dysfunction associated with cardiac hypertrophy (Tagawa et al, 1997). The integrated nature of biolological architecture also helps to explain why cardiac diseases and developmental abnormalities can be caused by mutations in various ostensibly unrelated molecules, including integrins, cytoskeletal filaments, ion channels, or nuclear components (Ingber, 2003a).…”

Tensegrity I. Cell structure and hierarchical systems biology

“…Experiments analyzing the effects of ECM adhesion and mechanical forces on microtubule polymerization in various adherent cells (Joshi et al, 1985;Dennerll et al, 1988;Dennerll et al, 1989;Lamoureux et al, 1990;Mooney et al, 1994;Putnam et al, 1998;Putnam et al, 2001;Kaverina et al, 2002) and a thermodynamic model of microtubule regulation ) support this notion. This may explain why microtubules did not appear to contribute significantly to smooth muscle cell mechanics in a study in which these cells were held under external tension (Obara et al, 2000), whereas in other studies they were found to play an important mechanical role in both smooth muscle cells (Wang et al, 2001;Stamenovic et al, 2002) and cardiac muscle cells (Tagawa et al, 1997).…”

Tensegrity II. How structural networks influence cellular information processing networks

“…It also may provide a molecular basis for gravity sensing (Ingber, 1999;Yoder et al, 2001) and control of circadian rhythmicity (Shweiki, 1999) in both animals and plants. In addition, tensegrity may help to explain why cellular components that are not directly involved in actomyosin-based tension generation, such as microtubules, intermediate filaments and ECM, can contribute significantly to contractile function in various cell types, including cardiac myocytes, vascular smooth muscle and skeletal muscle (Northover and Northover, 1993;Tsutsui et al, 1993;Lee et al, 1997;Tagawa et al, 1997;D'Angelo et al, 1997;Eckes et al, 1998;Gillis, 1999;Wang and Stamenovic, 2000;Keller et al, 2001;Balogh et al, 2002;Loufrani et al, 2002) as well as to control of permeability barrier function in endothelia (Moy et al, 1998).…”