CN-121971625-A - Use of SOAT A inhibitor in preparing medicine for preventing and treating cardiac hypertrophy related diseases

Abstract

The invention relates to an application of SOAT inhibitor in preparing a medicament for preventing and treating related diseases of cardiac hypertrophy, belonging to the technical field of biological medicines. The invention provides an application of SOAT A inhibitor in preparing medicines for preventing and treating related diseases of cardiac hypertrophy. The invention discovers the relation between SOAT gene and cardiac hypertrophy, further elucidates the mechanism, restores the heart size by inhibiting SOAT gene or protein activity thereof, remarkably inhibits the cross-sectional area of cardiac myocytes, improves cardiac fibrosis, and suppresses the disease progression of pathological cardiac hypertrophy. The invention also screens and provides SOAT inhibitors, including small molecular compounds F0808-1832, to inhibit SOAT gene expression and protein activity thereof, lays a solid theoretical foundation for preventing and treating related diseases of cardiac hypertrophy, and provides medicaments with good treatment effect.

Inventors

• LI HONGLIANG
• ZHANG XIAOJING
• YANG HAILONG
• HU YUFENG

Assignees

• 赣南创新与转化医学研究院

Dates

Publication Date

20260505

Application Date

20260309

Claims (10)

1. The SOAT1 inhibitor is applied to the preparation of medicines for preventing and treating diseases related to myocardial hypertrophy.
2. 2. The use of claim 1, wherein the SOAT inhibitor comprises a compound having a structural formula comprising at least one of formulas I to VIII, wherein formulas I to VIII are as follows: I; II; III; IV; V; VI; VII; VIII。
3. 3. the use of claim 1, wherein the SOAT inhibitor comprises an RNA that reduces SOAT1 gene expression, a vector that expresses said RNA, or an adenovirus that contains said vector.
4. 4. The use according to claim 3, wherein the RNA comprises shRNA or sgRNA, the nucleotide sequences of the shRNA are shown in SEQ ID NOs 1 and 2, and the nucleotide sequence of the sgRNA is shown in SEQ ID NOs 3 to 5.
5. 5. The use of claim 1, wherein the SOAT inhibitor comprises an agent that reduces SOAT1 protein activity.
6. 6. The use of claim 5, wherein the agent comprises a nucleic acid molecule, a vector expressing the nucleic acid molecule, or an adenovirus comprising the vector.
7. 7. The use of claim 5, wherein the agent that reduces SOAT protein activity is an agent that mutates histidine at position 455 of SOAT1 protein to alanine.
8. 8. The use of claim 1, wherein the medicament inhibits an increase in cardiomyocyte cross-sectional area.
9. 9. The use of claim 1, wherein the medicament reduces myocardial fibrosis.
10. 10. The use of claim 1, wherein the cardiac hypertrophy related disorder comprises at least one of cardiac dysfunction, myocardial fibrosis, supraventricular tachycardia, ventricular arrhythmia, atrial fibrillation, heart failure, mitral insufficiency, aortic stenosis, abnormal separation of heart walls, ventricular outflow tract obstruction, or sudden death.

Description

Use of SOAT A inhibitor in preparing medicine for preventing and treating cardiac hypertrophy related diseases Technical Field The invention relates to the technical field of biological medicines, in particular to application of SOAT inhibitor in preparing medicines for preventing and treating related diseases of cardiac hypertrophy. Background When the heart is stimulated by various factors, such as injury, pressure overload or ischemia, it exhibits adaptive hypertrophy growth, characterized by increased post-cardiac load and weight, and increased myocardial cell volume to maintain normal systolic and diastolic function. However, prolonged overload stimulation may lead to pathological myocardial hypertrophy, i.e. the transition of the myocardium from compensatory hypertrophy to decompensated hypertrophy. At this time, the ventricle is expanded and contracted to be dysfunctional, which may finally lead to arrhythmia, heart failure, sudden death and other adverse events. Pathologic myocardial hypertrophy is characterized by irreversible cardiomyocyte hypertrophy, sarcomere disorders, fibrosis, and inflammatory infiltrates. Although the molecular mechanisms of pathologic myocardial hypertrophy have been widely studied, viable therapeutic targets and strategies to prevent or reverse its adverse progression remain far from satisfactory. Sterol O-acyltransferase 1 (Sterol O-ACYLTRANSFERASE 1, SOAT1) is a sterol esterifying enzyme, which is mainly used to esterify free cholesterol into esterified cholesterol and store it as lipid droplets in cells. In recent years, a great deal of research has demonstrated that cholesterol metabolic disorders are closely related to the pathogenesis of heart failure. Plasma cholesterol levels are an independent risk factor for cardiovascular adverse events. However, it is not clear that there is a molecular link between cholesterol metabolism in the cardiomyocytes and the pathophysiological mechanisms of pathological cardiac hypertrophy. Furthermore, the function of SOAT1 in heart failure is not yet known as a key enzyme regulating cholesterol metabolism. At present, a molecular target related to myocardial hypertrophy is needed to be found so as to develop related targeted drugs and inhibit the related disease process of myocardial hypertrophy. Disclosure of Invention The invention aims to overcome the defects of the prior art, determines the connection between SOAT gene and myocardial hypertrophy and related diseases, and provides application of SOAT1 inhibitor in preparing medicaments for preventing and treating myocardial hypertrophy related diseases. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: in a first aspect, the present invention provides the use of a SOAT inhibitor in the manufacture of a medicament for the treatment of a cardiac hypertrophy related disease. According to the invention, by constructing a SOAT gene over-expression or knock-down myocardial cell hypertrophy model, the influence of SOAT gene on myocardial cell hypertrophy is analyzed by using Western Blot, qRT-PCR, immunofluorescence and other experiments. The result shows that the knock-down SOAT gene can obviously inhibit the expression of the myocardial hypertrophy marker genes such as Anp, bnp, myh and the like in myocardial cells, lighten the area increase of the myocardial cells induced by PE stimulation, and prove that SOAT1 is highly related to myocardial cell hypertrophy, and inhibit SOAT1 gene expression can improve myocardial cell hypertrophy. According to the invention, the myocardial cells of SOAT enzyme inactivation mutants are constructed, after PE stimulation, the over-expression of SOAT1 can promote myocardial hypertrophy, and after SOAT enzyme activity mutation, the myocardial hypertrophy promotion effect is lost, so that SOAT1 plays a role in promoting myocardial hypertrophy by relying on enzyme activity. The invention constructs SOAT myocardial cell specific knockout mice, and the aortic arch constriction operation shows that the knockout SOAT1 gene can restore the heart size, reduce the myocardial cell cross-sectional area and improve myocardial fibrosis, thus indicating that inhibiting SOAT1 gene expression can improve pathological myocardial hypertrophy of mice. Further, the SOAT1 inhibitor comprises a compound, wherein the structural formula of the compound comprises at least one of the formulas I-VIII, and the formulas I-VIII are shown as follows: I; II; III; IV; V; VI; VII; VIII。 further, the SOAT inhibitor includes an RNA that reduces SOAT1 gene expression, a vector that expresses the RNA, or an adenovirus that contains the vector. Furthermore, the RNA comprises shRNA or sgRNA, the nucleotide sequence of the shRNA is shown as SEQ ID NO.1 and 2, and the nucleotide sequence of the sgRNA is shown as SEQ ID NO. 3-5. Further, the SOAT inhibitor includes an agent that reduces SOAT1 protein activity. Still further, the agent comprises