1b) expression in the heart tissues, peaking between day 3 and day 5 after myocardial infarction (Fig. To evaluate the effect of MARK4 in the setting of ischaemic heart disease, we used a mouse model of permanent left anterior descending coronary artery ligation to induce a large myocardial infarction 22, 23 (Extended Data Fig. Here we examined whether MARK4 regulates the function of the failing cardiomyocyte through modulation of microtubule detyrosination. MARK4 is expressed in the heart 20 however, the role of MARK4 in the cardiomyocyte has not been studied.
The phosphorylation of MAPs triggered by MARK induces conformational changes that alter the association of MAPs with microtubules, and thereby regulates microtubule dynamics 19, 20, 21. MARK4 is an evolutionarily conserved serine–threonine kinase 17, 18 that is known to phosphorylate MAPs including tau, MAP2 and MAP4, on KXGS motifs within their microtubule-binding repeats 19, 20, 21. MAP4 dephosphorylation on the microtubule network has previously been described in a feline model of pressure-overload cardiac hypertrophy 16, but the relationship between MAP4 phosphorylation and microtubule detyrosination has not been examined. MAP4 is expressed in cardiomyocytes and the level of MAP4 significantly increases in human hearts with cardiomyopathy 7. Microtubule stability is regulated by microtubule-associated proteins (MAPs), including classical MAPs such as MAP2, MAP4 and tau 15. However, the regulatory mechanisms of this system are still poorly understood. Structural and biophysical studies have suggested that VASH interacts with the C-terminal tail of α-tubulin 12, 13, 14. Depletion of VASH1 increases the speed of contraction and relaxation in failing human cardiomyocytes 11. VASH1 or VASH2, coupled to a small vasohibin-binding protein (SVBP), forms tubulin carboxypeptidases (TCPs) that are capable of tubulin detyrosination 9, 10. Microtubule detyrosination, which is associated with desmin at force-generating sarcomeres 5, is upregulated in failing hearts of patients with ischaemic cardiomyopathy 5, 7 and hypertrophic cardiomyopathies 5, 7, 8, and suppression of microtubule detyrosination improves contractility in failing cardiomyocytes 7. Myocardial infarction-the main cause of ischaemic heart disease and chronic heart failure-is a serious ischaemic syndrome in which the blood supply to the heart is blocked, thus causing substantial death of myocardial cells and loss of function in the remaining viable cells 6. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility 5.
More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure 2, 3 or have shown a very modest reduction of risk of heart failure 4. Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate 1. LT drops Items.Myocardial infarction is a major cause of premature death in adults. BACK GRIPS are used for dropping & using Items. Fully tested control scheme that keeps 90% of the 360 layout. "description" "COMFORTABLE CONTROLS / NAMED BUTTON BINDING.
0 kommentar(er)
