Introduction
Protein tyrosine phosphatase family and substrate specificity
Role of PTPs in cardiac development and diseases
PTP | Animal model | Effect on the cardiovascular system | Comments | Reference |
---|---|---|---|---|
PTP1B (PTPN1 gene) | Global PTP1B deletion in Balb/c mice | PTP1B deficiency enhances the effects of leptin on arterial pressure | • Normal heart/body weight ratio, insulin, leptin, glucose, and triglyceride levels in fasting condition • Increased blood pressure at base line and after leptin infusion • Blunted response to phenylephrine • Reduction of aortic contraction after phenylephrine injection | [37] |
Global PTP1B deletion in Balb/c mice or PTP1B chemical inhibition | PTP1B deficiency protects against chronic heart failure after myocardial infarction | • No phenotype at baseline • Improvement of cardiac contractility and reduction of fibrosis and hypertrophy • Preserved endothelial function | [38] | |
Endothelial-specific deletion of PTP1B in mice | PTP1B deletion in endothelium improves angiogenesis and protects against pressure overload induced heart failure | • Improved systolic function and reduced cardiac hypertrophy of PTP1B-deficient mice • Preserved capillary density, reduced apoptosis and fibrosis • Improved cardiac VEGF signaling | ||
Global PTP1B deletion in Balb/c mice | PTP1B deletion enhances angiogenesis and arteriogenesis after myocardial infarction | • Increased capillary density • Increased VEGFR2 activation • Reduced diastolic dysfunction | [41] | |
SHP2 (PTPN11 gene) | Xenopus cardiac explants treated with the SPH2 inhibitor NSC-87877 | SHP2 is required for the maintenance of cardiac progenitor cells | • Reduction of MHC expression, lack of early cardiac markers and of and pharyngeal mesoderm in cardiac progenitors • SHP2 controls Ca2+ transient and oscillation in fibroblasts and in cardiac myocytes • SHP2 is positioned downstream of FGF | [42] |
Genetic deletion of SHP2 exon 3 in mice (SHP2Ex3−/−) | Gain-of-function/Noonan syndrome SHP2 mutants increase Ca2+ oscillations and impair NFAT signaling in fibroblasts and cardiomyocytes | • SHP2 is required for Ca2+ oscillations in response to FGF-2 in fibroblasts and cardiomyocytes • Gain-of-function SHP2 mutants disrupt the Ca2+ oscillatory control of NFAT | [43] | |
Cardiac specific deletion of SHP2 | SHP2 deletion in cardiac muscle causes dilated cardiomyopathy with no hypertrophy | • Defective ERK/MAPK activity and hyper-activation of Rho signaling after agonist treatment of cardiomyocytes and pressure overload | [44] | |
Overexpression of Noonan syndrome SHP2-Q79R in mice | Congenital heart defects are rescued by ERK1/2 activation | • Impaired cycling activity, ventricular non-compaction, and septal defects • Activation of ERK1/2 | [45] | |
Muscle specific deletion of SHP2 | SHP2 deletion in skeletal muscle causes dilated cardiomyopathy, heart failure, and premature death | • Severe dilated cardiomyopathy resulting in heart failure and death • Associated with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells • Upregulation of PI3K/Akt, ERK5, and STAT3 in cardiomyocytes | [46] | |
Knockin SHP2-Y279C mutation in mice | Recapitulation of LEOPARD syndrome by expression of the SHP2-Y279C mutation. Cardiomyopathy reversed by rapamycin treatment | • Increased binding of SHP2 to IRS1 • Decreased SHP2 catalytic activity, and blunted ERK/MAPK activation and increased AKT and mTOR after agonist treatment | [18] | |
Overexpression of SHP2-Q510E in mice | Early onset hypertrophic cardiomyopathy | • Impaired contractile function, thickening of the ventricular wall • Activation of AKT and mTOR • Rescue of cardiomyopathy by rapamycin treatment at the post-natal stage | [3] | |
Expression of LEOPARD and NOON SYNDROM mutations in zebrafish | Impaired early heart development and function | • Activation of MAPK in embryos expressing the mutations | [47] | |
Knockin SHP2-Y279C mutation in mice | Expression of SHP2-Y279C causes developmental defects and adult onset HCM in mice originating from the endocardium | • Reduced trabeculation and valvular hyperplasia in embryonic hearts expressing SHP2-Y279C and in the heart of mice with endothelial-specific but not myocardial-specific SHP2-Y279C expression • Endothelial-specific expression of SHP2-Y279C induces cardiac hypertrophy in the adult heart • Myocardial-specific SHP2-Y279C expression causes ventricular septal defects • Abnormal AKT activity and decreased forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling | [48] | |
LMWPTP (ACP1 gene) | Global deletion of ACP1 in mice | ACP1 deletion protects against pathological cardiac stress | • Attenuated fibrosis and preserved cardiac contractility • Increased IR phosphorylation, PKA, and Ephrin expression • Reduced CaMKII expression | [4] |
PTP1B
SHP2
LMWPTP
PTP inhibitors as potential new therapeutic for cardiac diseases
Inhibitor | Targeted PTP | Effect on cardiovascular system | Model | Advantages | Disadvantages | Reference |
---|---|---|---|---|---|---|
Vanadate | PTPs | • Selective | • Non-specific | [92] | ||
Vanadyl sulfate | PTPs | Cardioprotection against ischemia reperfusion | • Coronary occlusion in rats | • Reduction of infarct size and of left ventricular end diastolic pressure • Improvement of left ventricular developed pressure and contractility • Inhibition of apoptosis • Increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt | • Gastrointestinal side effects | |
Vanadyl sulfate | PTPs | Alteration of proteins involved in early insulin signaling in skeletal muscle. No global change in protein phosphatase activity | • Human with diabetes mellitus | • Increased basal levels of IR, Shc, and IRS-1 tyrosine phosphorylation and IRS-1 • No effect on insulin | • Gastrointestinal side effects at 150 and 300 mg | [94] |
AS279, AS098, AS713 | PTP1B and SHP2 | Improved endothelial dysfunction in peripheral mesenteric arteries | • Mice with coronary ligation | • Selective inhibitors • Transient early eNOS phosphorylation and AKT phosphorylation | • Relatively good selectivity | [95] |
AS279 | PTP1B | Protects against chronic heart failure after myocardial infarction | • Mice | • Reduced adverse ventricular remodeling • Improved LV function and cardiac contractility • Reduced fibrosis and cardiac hypertrophy • Preserved endothelial function • No effect on glucose level | [38] | |
NSC-87877 | SHP2 | SHP2 is required for the maintenance of cardiac progenitor cells | • Xenopus heart explants | • Reduction of MHC expression, lack of early cardiac markers and of and pharyngeal mesoderm in cardiac progenitors • SHP2 controls Ca2+ transient and oscillation in fibroblasts and in cardiac myocytes • SHP2 is positioned downstream of FGF | [42] | |
PHPS1 | SHP2 | Inhibits cardiac hypertrophy induced by SHP2-Q510E and SHP2-Y279C mutations | • Cardiomyocytes and mice | • Normalization of the size of cardiomyocytes expressing SHP2-Q510A and SHP2-Y279C • Restoration of AKT and mTOR levels | • Specificity | [96] |
Chromones | LMWPTP and PTP1B | • High activity | [97] | |||
Compound 23 | LMWPTP | Small-molecule inhibitor reverses high fat diet-induced obesity | • Mice | • Improves glucose tolerance • Increases IR phosphorylation in the liver • Orally bioavailable • Uncompetitive mode of action • High selectivity | • Not reported | [98] |