Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure‐Overloaded Hearts

Abstract

BackgroundInsulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in cardiac insulin response and mitochondrial function in a model of pressure overload‐induced heart failure.Methods and ResultsRats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks. This contractile impairment was accompanied by mitochondrial dysfunction as shown by markedly reduced state 3 respiration of isolated mitochondria. Aortic banding did not affect systemic insulin response. However, insulin‐stimulated cardiac glucose uptake and glucose oxidation were significantly diminished at 10 and 20 weeks, which indicates cardiac insulin resistance starting before the onset of mitochondrial and contractile dysfunction. The impaired cardiac insulin action was related to a decrease in insulin‐stimulated phosphorylation of insulin receptor β. Consistently, we found elevated activity of protein tyrosine phosphatase 1B (PTP1B) at 10 and 20 weeks, which may blunt insulin action by dephosphorylating insulin receptor β. PTP1B activity was also significantly increased in left ventricular samples of patients with systolic dysfunction undergoing aortic valve replacement because of aortic stenosis.ConclusionsPressure overload causes cardiac insulin resistance that precedes and accompanies mitochondrial and systolic dysfunction. Activation of PTP1B in the heart is associated with heart failure in both rats and humans and may account for cardiac insulin resistance. PTP1B may be a potential target to modulate insulin sensitivity and contractile function in the failing heart.

Altered Tyrosine Phosphorylation of Cardiac Proteins Prompts Contractile Dysfunction in Hypertrophic Cardiomyopathy

“…The TgErbB2 mouse model is important because it shows pronounced cardiac hypertrophy at an early age, sarcomere dysfunction, and abnormal calcium handling 16 , thus connecting the tyrosine kinase pathway and tyrosine phosphorylation to cardiac hypertrophy. While ErbB2 was previously reported to be overexpressed ~40-fold in TgErbB2 hearts 12 , the tandem mass tagging quantitative proteomics data, which allowed normalization of the peptide phosphorylation signal to total protein levels of ErbB2, revealed that the phosphorylation level of ErbB2-Y1006 peptide is reduced in this model (Fig.5G). The low stoichiometry of phosphorylated:non-phosphorylated ErbB2 may account for the apparent lack of alteration of the ErbB signaling pathway.…”

“…Moreover, mutations at the level of tyrosine-protein phosphatase non-receptor type 11 (PTPN11) can lead to HCM or dilated cardiomyopathy (DCM) 10,11 . In the heart, PTPN11 likely plays a role in systolic dysfunction produced by pressure-overload 12 . Another tyrosine phosphatase is associated with cardiac pathophysiology, specifically acid phosphatase 1 (ACP1):-the deletion of ACP1 results in a protection against stress-induced cardiomyopathy 13 .…”

The protective role of MiR-206 in regulating cardiomyocytes apoptosis induced by ischemic injury by targeting PTP1B

“…It was also identified as a key mediator for metabolism and oncogenesis [41]. A recent study pointed out that PTP1B could also be a potential target to modulate cardiac insulin sensitivity and contractile function in the failing heart [22]. It is not surprising that PTP1B and its protein substrate targets together regulate a complex signaling network.…”

“…Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed phosphatase and it has been identified as a pivotal modulator of insulin signaling pathways as it can dephosphorylate the insulin receptor and inactivate insulin signaling [18]. Recent studies also illustrated that increased activity of PTP1B was associated with the regulation of insulin sensitivity and contractile function, the pathophysiology of endothelial dysfunction, and cardiac dysfunction in heart failure [19][20][21][22][23]. The regulation of PTP1B by miR-210 was investigated in MI in mice and it showed that miR-210 directly targets PTP1B and the repression of PTP1B lead to improved angiogenesis and reduced apoptosis, which in turn improves the cardiac functions [24].…”

Inhibiting the Inhibitors, PTP1B as a Therapeutic Target in Myocardial Infarction

“…21 In the heart specifically, PTP1B has been suggested to play an important role in regulating contractile function (reviewed in 22 ) which may at least in part, be due to the regulation of insulin signaling which itself is blunted in the failing heart concomitantly with enhanced PTP1B activity. 11 Some mechanisms that are directly implicated therefore include insulin-mediated metabolic regulation and cardioprotection, 11,23 increased tissue perfusion through enhanced angiogenesis, 13 endothelial protection which may be nitric oxide dependent 6,13,24 and improved contractile function. 22 Insulin-independent mechanisms also exist, and indeed, PTP1B has many other potential targets.…”