PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease

Abstract

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.

Nicotinic acid affects cytoskeleton remodeling via increasing the activity of gelsolin

“…It has been demonstrated that the gelsolin‐PI3Kα (p110α) complex plays an important role in the regulation of gelsolin function in cytoskeletal remodeling (Patel et al, ). Therefore, we next investigated the effect of NA treatment on the gelsolin‐PI3Kα (p110α) interaction.…”

“…Studies have shown that PI3Kα inhibits gelsolin activity by converting PIP2 to PIP3, and actin filament assembly could be functionally rescued with PIP3 through activating gelsolin in cardiomyocytes (Patel et al, ). Our results showed that NA treatment significantly inhibited the interaction between PI3Kα (p110α) and gelsolin.…”

“…Previous studies have found that NA could modulate the intracellular calcium concentration and disassemble the cytoskeleton (J. Li, Li, Zhang, Niu, & Shi, ). Further, the phosphoinositide 3‐kinase (PI3K) α‐regulated gelsolin activity is a key determinant of cardiac cytoskeletal remodeling (Patel et al, ). Based on these preliminary foundations, this paper aimed to reveal the underlying mechanism of NA‐induced cytoskeleton remodeling, which helps to better understand the inhibition process of NA on angiogenesis.…”

“…Li, Li, Zhang, Niu, & Shi, 2014). Further, the phosphoinositide 3-kinase (PI3K) α-regulated gelsolin activity is a key determinant of cardiac cytoskeletal remodeling (Patel et al, 2018).…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…Furthermore, PI3Kα activity protects the heart against myocardial infarction‐induced heart failure [191], can improve the function of a failing heart, is important for exercise‐induced cardioprotection [192], and can protect against heart disease in response to dilated cardiomyopathy and acute pressure overload [193,194]. PI3Kα also negatively regulates gelsolin‐activity to suppress gelsolin's actin‐severing activity that contributes to cardiac remodelling in heart failure [195]. PI3Kα's role in mediating insulin signalling to L‐type calcium channels to regulate calcium currents in cardiac myocytes is a key mechanism underpinning the importance of this Class I PI3K isoform in the heart, while both PI3Kα and PI3Kβ support cardiac structure and organisation via regulation of junctophilin‐2 localisation and T‐tubule organisation [152, 196, 197].…”