Single-Stranded DNA-Binding Protein 1 Abrogates Cardiac Fibroblast Proliferation and Collagen Expression Induced by Angiotensin II

Abstract

Angiotensin II (Ang II), an effective component of renin-angiotensin system, plays a pivotal role in cardiac fibrosis, which may further contribute to heart failure. Single-stranded DNA-binding protein 1 (SSBP1), a DNA damage response protein, regulates both mitochondrial function and extracellular matrix remodeling. In this study, we aim to investigate the role of SSBP1 in cardiac fibrosis that is induced by Ang II. We infused C57BL/ 6J mice with vehicle or Ang II and valsartan using implanted osmotic mini-pumps. Moreover, heart function was examined by echocardiography and cardiac fibrosis was analyzed via picrosirus red staining. The expression of COL1A1, COL3A1, SSBP1, p53, Nox1, and Nox4 was analyzed via qRT-PCR and/or immunoblots. The SSBP1 expression was manipulated via SSBP1 shRNA and pcDNA3.1/SSBP1 plasmids, while the p53 expression was enhanced via AdCMV-p53 infection. The exposure to Ang II increased the mouse heart weight, systolic blood pressure, interventricular septal thickness diastolic (IVSTD) and left ventricular end posterior wall dimension diastolic (LVPWD), which were counteracted by valsartan. While cardiac fibrosis was induced with Ang II treatment, it was relieved using valsartan. Furthermore, Ang II treatment caused mitochondrial dysfunction, oxidative stress, and down-regulated SSBP1 expression. The knockdown of SSBP1 increased cardiac fibroblast proliferation, collagen expression, and decreased p53 expression, which was impeded via SSBP1 overexpression. Moreover, the forced expression of p53 abated the fibroblast proliferation and collagen expression that was induced by Ang II. To summarize, SSBP1 was down-regulated by Ang II and implicated in cardiac fibroblast proliferation and collagen expression partly via the p53 protein.

The Association of Ascorbic Acid, Deferoxamine and N-Acetylcysteine Improves Cardiac Fibroblast Viability and Cellular Function Associated with Tissue Repair Damaged by Simulated Ischemia/Reperfusion

“…Among these, type I collagen is widely expressed in cardiac tissue of mammals and forms thick and stiff fibers [26]. Angiotensin II is a peptide known to elicit cardiac fibrosis [51,52] by stimulating CF collagen production and secretion [53,54]. In our CF in vitro model, sI/R prevented the increase of pro-collagen I synthesis triggered by angiotensin II and did not induce pro-collagen I production by itself.…”

Exploring Molecular Mechanism of Huangqi in Treating Heart Failure Using Network Pharmacology

“…NOS3 and NOS2 have superoxide metabolism, nitric oxide reaction, and regulation of arterial blood pressure [47]. SOD1, TGF1, TNF, RAF1, and TP53 participate in the process of cardiac remodeling [48][49][50][51][52]. Attenuation of mitochondrial translocation of HSPB1 resulting in damage to mitochondrial energy production capacity, elevation of HSPB1 level, or decrease in CCL2 expression helps to maintain mitochondrial function to improve systolic function [53,54].…”

The Impact of Sacrubitril/Valsartan on Clinical Treatment and hs-cTnT and NT-ProBNP Serum Levels and the Left Ventricular Function in Patients with Chronic Heart Failure

“…23) The development of heart failure is also inseparable from the excessive activa-tion of RAAS, which is able to increase inflammatory reactions and results in cardiomyocyte apoptosis and eventually cardiac remodeling. 4) In addition, it can increase the level of biologically active natriuretic peptide. Through the inhibitory effect of sacrubitril on neprilysin, reduced degradation of natriuretic peptide and inhibition of RAAS by the ARB valsartan, the combined effect of the two drugs could dilate vessels, promote natriuresis, further inhibit cardiac remodeling, and finally improve the survival rate of patients with heart failure.…”

“…Developed by Novartis, it has been on the market in China since July 2017 as an innovative drug for the treat-ment of CHF. 4,5) In our study, we compared treatment with sacrubitril/ valsartan to that of valsartan, combined the general treatments with aldosterone antagonist and β-blocker, observed clinical effects, assayed the levels of hs-cTnT and NT-ProBNP in serum, and measured the value of LAD, LVEDD, and LVEF in order to figure out if sacrubitril/ valsartan could improve levels of serum hs-cTnT and NT-ProBNP and the left ventricular function.…”