Integrin signalling: The tug-of-war in heart hypertrophy

Abstract

The mechanical stress imposed by hemodynamic overload on heart walls is a primary event in triggering the cardiac hypertrophic response. Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. In fact, integrins, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy program. In this review, we will discuss the role of the muscle-specific integrin isoform beta1D and of associated proteins such as FAK, melusin, vinculin, zyxin, VASP, and migfilin that are the most upstream elements ("initiators") activated by mechanical strain. These molecules trigger a coordinated downstream signaling cascade involving proteins such as AKT, RAS, and MAPKs that execute the biochemical program leading to cardiomyocyte hypertrophy. Better understanding of the functional role of the initiator elements is of key importance to developing novel strategies to control cardiac hypertrophy and prevent heart failure.

FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

“…Further, we analysed the phosphorylation status of other kinases, since melusin (the expression of which is reduced through FRZB silencing) phosphorylates ERK1/2 (Ref. 17), as well as Akt kinase (which in turn phosphorylates the glycogen synthase kinase 3). The total amount of Akt was not different after silencing the FRZB gene, but the signal corresponding to phosphorylated Akt was lower.…”

Integrins in the Development and Pathology of Skeletal Muscle

“…These changes led to an enlarged left ventricular chamber, a decrease in contractile function and eventually cardiac arrest, and may involve signaling through GSK3 and Akt, as phosphorylation in these proteins was reduced. Interestingly, unlike what is observed in FAK-deficient mice, infusion with angiotensin II or phenylephrine did not cause an aberrant hypertrophic response in melusin-null mice, indicating that melusin is required to specifically sense mechanical but not biohemical stimuli (Brancaccio et al, 2006;. No overt defects in skeletal muscle were observed in melusing-knockout mice.…”

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

“…As a class of membrane receptors, integrins are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes 31. In the integrin initiating signaling pathway, clustering of integrins leads to the recruitment of FAK to the newly formed focal adhesion which results in auto‐phosphorylation and concomitant activation of FAK 30, 32.…”