Cardiac troponin I: the "commander" of myocardial cells and the key target for the treatment of heart failure

Cardiac troponin I: the "commander" of myocardial cells and the key target for the treatment of heart failure

In the microscopic world of our human body, every beat of the heart is inseparable from an important molecule - cardiac troponin I (cTnI). It is like the "commander" of myocardial cells, playing a key role in the contraction and relaxation of the heart, and its interaction with a protein kinase called TNNI3K has brought new hope for the treatment of heart failure.

Cardiac troponin I is a core regulatory element on the thin filaments of myocardial cells that senses calcium ion concentration and activates myocardial contraction. It mainly has multiple phosphorylation regulatory sites, among which Ser23/24, Ser43/45 at the N-terminus and Thr144 and Ser149 at the C-terminus are particularly important. The phosphorylation of Ser23/24 is mainly regulated by kinases such as protein kinase A (PKA), protein kinase G (PKG) and protein kinase D (PKD), which is the basis for the positive inotropic effect of β-adrenergic induction of myocardium, and can increase myocardial compensatory relaxation and contraction. However, in heart failure, cTnI Ser23/24 phosphorylation is significantly reduced, resulting in "insufficient phosphorylation". This "insufficient phosphorylation" increases the calcium sensitivity of myofibril filaments and is closely related to diastolic dysfunction in failing myocardium.

TNNI3K, as the only known protein kinase specifically expressed in the heart, is closely related to cTnI. The serine-rich domain at the C-terminus of TNNI3K protein directly interacts with cTnI, and TNNI3K can upregulate the phosphorylation level of cTnI protein Ser23/24 in vivo and in vitro. This means that TNNI3K may participate in the remodeling of cardiac structure and function by regulating the phosphorylation level of cTnI. In the early stages of pathological conditions such as myocardial injury or hypertension, myocardial cells compensatory enlargement, heart weight increase, ventricular wall thickening, and sarcomere rearrangement are performed to balance ventricular wall pressure and maintain cardiac function. However, if pathological stimulation persists for a long time, the heart will decompensate, the ventricle will dilate, the ventricular wall will thin, and the systolic and (or) diastolic function will be impaired, gradually turning into heart failure. In this process, abnormal activation of TNNI3K and disordered regulation of cTnI may be one of the important factors in the occurrence and development of myocardial remodeling and heart failure.

In recent years, scientists have continued to deepen their research on TNNI3K. They found that TNNI3K plays an important role in the occurrence and development of various myocardial remodeling. In the model of increased left ventricular afterload and left ventricular remodeling induced by aortic coarctation surgery in rats, the expression of TNNI3K gene in the left ventricle of rats was first downregulated and then upregulated. In the model of angiotensin II and phenylephrine stimulating rat neonatal cardiomyocyte hypertrophy, TNNI3K was also first downregulated and then upregulated, suggesting that TNNI3K is involved in the course of myocardial hypertrophy. In addition, TNNI3K transgenic mice showed significant changes in heart-to-body weight ratio and myocardial remodeling phenotype, further confirming the important role of TNNI3K in myocardial remodeling.

Even more exciting is that highly selective inhibitors of TNNI3K such as GSK854, 7-Deazapurines and GSK114 have shown good effects in animal models. These inhibitors are expected to regulate the phosphorylation level of cTnI and improve the function of cardiomyocytes by specifically inhibiting the activity of TNNI3K, thus providing a new strategy for the treatment of heart failure. Heart failure is one of the leading causes of death and disability worldwide, and it has brought a heavy economic burden to society and families. In my country, with the aging of the population, the incidence of heart failure has increased year by year and has become a major public health problem. Therefore, in-depth research on the interaction between TNNI3K and cTnI and its mechanism of action in myocardial remodeling and heart failure is of great significance for the development of new drugs for the treatment of heart failure.

In the future, with the continuous advancement of science and technology, we believe that scientists will be able to more comprehensively reveal the complex relationship between TNNI3K and cTnI, as well as their fine regulatory mechanism in cardiomyocytes. This will bring more hope to patients with heart failure, and is expected to improve the prognosis of heart failure, improve the quality of life of patients, and reduce the burden on society and families. Let us look forward to that day, and look forward to greater breakthroughs in the treatment of heart failure, so that every beat of the heart can be healthier and stronger.