Activated Cell Survival Cascade in Tako-Tsubo Cardiomyopathy
Activated Cell Survival Cascade in Tako-Tsubo Cardiomyopathy
Aims Tako-Tsubo cardiomyopathy (TTC) is characterized by rapid regeneration of contractile dysfunction. From recent studies it is known that excessive catecholamine levels due to emotional or physical stress might play a central role. After sympathetic activation, the PIK3/AKT pathway is a key regulator of many cellular responses, including cytoprotective effects. Thus, the purpose of this study was to investigate whether the PIK3/AKT pathway plays a pivotal role in TTC.
Methods and results A total of 16 consecutive patients diagnosed with TTC were studied. Left ventricular biopsies were taken during the acute phase and after functional recovery. Specimens were examined by quantitative RT–PCR and western blotting. Representative genes of the PI3K/AKT pathway (PIK3-R1, PTEN, GSK3β, mTOR, PP2A, eIF4E) were compared with left ventricular controls from non-transplanted healthy hearts. PI3K expression was increased during the acute phase and after functional recovery. AKT protein levels were unaltered, but phosphorylation significantly increased during the acute phase. Both PTEN (PI3K antagonist) and PP2 (unspecific phosphatase) were down-regulated. Phosphorylation of the PI3K/AKT downstream target mTOR was increased, while expression of both GSK3 isoforms was decreased. The Bax/Bcl2 ratio was increased in the acute and recovery phases.
Conclusion PI3K/AKT signalling is activated in TTC. This activated cell survival cascade might protect cardiomyocytes from cell death and also contribute to rapid regeneration in TTC.
Tako-Tsubo cardiomyopathy (TTC), also known as 'left ventricular apical ballooning' or 'broken heart syndrome', is characterized by contractile dysfunction of the apical and/or midventricular areas, which results in a significantly lowered ejection fraction (EF). The shape of the left ventricle resembles a traditional Japanese octopus trap, the 'tako-tsubo'. Tako-Tsubo cardiomyopathy is triggered by severe emotional or physical stress.
The exact pathomechanism of TTC remains unknown, although several theories have been proposed by different groups. The most promising hypothesis involves the substantially elevated plasma catecholamine levels measured in TTC patients producing a catecholamine toxicity. Excess catecholamine levels can cause various alterations, including direct cell damage, synthesis of reactive oxygen species, alteration of the calcium-handling proteins, and redistribution of coronary blood flow via sympathetic vasoconstriction. However, recent data have shown that TTC has a very favourable prognosis, with functional recovery and almost complete reversal of the documented structural changes.
Gene expression profiling with microarray technique has demonstrated that genes coding for the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway proteins are differentially expressed in TTC. AKT is critical for postnatal cardiac growth and coronary angiogenesis. Also, its downstream targets, especially the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), are well-established regulators of metabolism, proliferation, and cell survival. Cell survival is achieved through various mechanisms: (1) direct inhibition of apoptosis, (2) inhibition of proapoptotic transcriptional factors, (3) enhancement of antiapoptotic transcriptional factors, and (4) enhancement of cell metabolism by inhibition of the GSK3.
The aim of this study was to evaluate whether the PI3K/AKT signalling pathway is activated in TTC, and if so, whether this has a cardioprotective effect by improving cell survival in TTC.
Abstract and Introduction
Abstract
Aims Tako-Tsubo cardiomyopathy (TTC) is characterized by rapid regeneration of contractile dysfunction. From recent studies it is known that excessive catecholamine levels due to emotional or physical stress might play a central role. After sympathetic activation, the PIK3/AKT pathway is a key regulator of many cellular responses, including cytoprotective effects. Thus, the purpose of this study was to investigate whether the PIK3/AKT pathway plays a pivotal role in TTC.
Methods and results A total of 16 consecutive patients diagnosed with TTC were studied. Left ventricular biopsies were taken during the acute phase and after functional recovery. Specimens were examined by quantitative RT–PCR and western blotting. Representative genes of the PI3K/AKT pathway (PIK3-R1, PTEN, GSK3β, mTOR, PP2A, eIF4E) were compared with left ventricular controls from non-transplanted healthy hearts. PI3K expression was increased during the acute phase and after functional recovery. AKT protein levels were unaltered, but phosphorylation significantly increased during the acute phase. Both PTEN (PI3K antagonist) and PP2 (unspecific phosphatase) were down-regulated. Phosphorylation of the PI3K/AKT downstream target mTOR was increased, while expression of both GSK3 isoforms was decreased. The Bax/Bcl2 ratio was increased in the acute and recovery phases.
Conclusion PI3K/AKT signalling is activated in TTC. This activated cell survival cascade might protect cardiomyocytes from cell death and also contribute to rapid regeneration in TTC.
Introduction
Tako-Tsubo cardiomyopathy (TTC), also known as 'left ventricular apical ballooning' or 'broken heart syndrome', is characterized by contractile dysfunction of the apical and/or midventricular areas, which results in a significantly lowered ejection fraction (EF). The shape of the left ventricle resembles a traditional Japanese octopus trap, the 'tako-tsubo'. Tako-Tsubo cardiomyopathy is triggered by severe emotional or physical stress.
The exact pathomechanism of TTC remains unknown, although several theories have been proposed by different groups. The most promising hypothesis involves the substantially elevated plasma catecholamine levels measured in TTC patients producing a catecholamine toxicity. Excess catecholamine levels can cause various alterations, including direct cell damage, synthesis of reactive oxygen species, alteration of the calcium-handling proteins, and redistribution of coronary blood flow via sympathetic vasoconstriction. However, recent data have shown that TTC has a very favourable prognosis, with functional recovery and almost complete reversal of the documented structural changes.
Gene expression profiling with microarray technique has demonstrated that genes coding for the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway proteins are differentially expressed in TTC. AKT is critical for postnatal cardiac growth and coronary angiogenesis. Also, its downstream targets, especially the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), are well-established regulators of metabolism, proliferation, and cell survival. Cell survival is achieved through various mechanisms: (1) direct inhibition of apoptosis, (2) inhibition of proapoptotic transcriptional factors, (3) enhancement of antiapoptotic transcriptional factors, and (4) enhancement of cell metabolism by inhibition of the GSK3.
The aim of this study was to evaluate whether the PI3K/AKT signalling pathway is activated in TTC, and if so, whether this has a cardioprotective effect by improving cell survival in TTC.
