Differential Regulation of ERK and mTOR Signaling Pathways in Failing Human Hearts
Authors: Autenried Rebecca , Weatherford Eric T. , Zhang Yuan , Kenny Helena C. , Pereira Renata O. , O’Neill Brian T. , Eyck Patrick Ten , Bedi Kenneth C. , Margulies Kenneth B. , Abel E. Dale 
Published: December 2020

STUCTURED ABSTRACT

Objectives

We hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into the pathophysiology of heart failure. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant.

Background

Pathologic ventricular remodeling accompanied by hypertrophic growth is a common characteristic of heart failure including in patients with diabetes. The contribution of aberrant insulin signaling in the pathophysiology of diabetes-associated heart failure and, ventricular hypertrophy is incompletely understood.

Methods

Hearts of twenty non-failing donor participants and thirty-one human cardiac transplant patients were assessed for insulin signaling. Samples were sorted into four groups: non-failing non-obese (NFN), non-failing obese (NFO), failing non-diabetic (FND), and failing diabetic (FDM). Ejection fraction was assessed by echocardiography and clinically relevant systolic dysfunction was defined as left ventricular ejection fraction <50%. A clinical diabetes diagnosis was obtained from chart review. As a proxy measure of prolonged glycemia, plasma fructosamine was determined by colorimetric assay. Insulin signaling, protein phosphorylation, and total protein levels were measured by immunoblot.

Results

When all groups were analyzed together, hyperglycemia correlated with increased cardiac size and decreased function. Cardiac size correlated with increased levels of insulin receptor (IRb) and phosphorylated ERK but with decreased levels of phosphorylated Akt and mTOR. IRb and p-Akt correlated with fructosamine, but p-ERK and p-mTOR did not. Cardiac hypertrophy correlated with decreased GLUT1 levels, increased Hexokinase I and repression mitochondrial complexes I, III and IV in concert with activation of AMPK.

Conclusions

Altered insulin signaling, characterized by increased IRb content, activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart. Similar divergence of insulin signaling pathways have been previously described in vascular smooth muscle.

CONDENSED ABSTRACT

We hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into pathophysiology. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant. We found that altered insulin signaling, characterized by increased IRb content and activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart.

HIGHLIGHTS

In this cross-sectional analysis of end-stage failing human cardiac tissue, hyperglycemia correlated with cardiac dysfunction and increased cardiac hypertrophy.

While myocardial insulin resistance may exist in the PI3K-Akt-mTOR pathway in end-stage failing human hearts, ERK signaling is induced, which may contribute to cardiac hypertrophy in a manner that is independent of plasma insulin.

Differential activation of branches of insulin signaling in human failing hearts, supports the concept of selective insulin resistance.

These findings have implications for the consequences of modulating systemic insulin sensitivity in patients with heart failure.