Intracellular and extracellular Cyclophilin a promote cardiac fibrosis through TGF-ß signaling in response to angiotensin â ¡.

Cardiac fibrosis is characterized by abnormal proliferation of cardiac fibroblasts (CFs) and ventricular remodeling, which finally leads to heart failure. Inflammation and oxidative stress play a central role in the development of cardiac fibrosis. CyPA (Cyclophilin A) is a main proinflammatory cytokine secreted under the conditions of oxidative stress. The mechanisms by which intracellular and extracellular CyPA interact with CFs are unclear. Male C57BL/6 J mice received angiotensin Ⅱ (Ang Ⅱ) or vehicle for 4 weeks. Inhibition of CyPA significantly reversed Ang Ⅱ-induced cardiac hypertrophy and fibrosis. Mechanically, TGF-ß (Transforming growth factor-ß) signaling was found to be an indispensable downstream factor of CyPA-mediated myofibroblast differentiation and proliferation. Furthermore, intracellular CyPA and extracellular CyPA activate TGF-ß signaling through NOD-like receptor protein 3 (NLRP3) inflammasome and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, respectively. Pharmacological inhibition of CyPA and its receptor CD147 implemented by Triptolide also attenuated the expression of TGF-ß signaling and cardiac fibrosis in Ang Ⅱ-model. These studies elucidate a novel mechanism by which CyPA promotes TGF-ß and its downstream signaling in CFs and identify CyPA (both intracellular and extracellular) as plausible therapeutic targets for preventing or treating cardiac fibrosis induced by chronic Ang Ⅱ stimulation.

Sirtuin 3: Emerging therapeutic target for cardiovascular diseases.

Acetylation is one of the most important methods of modification that lead to a change in the function of proteins. In humans, metabolic enzymes commonly undergo acetylation, which regulates the activities of metabolic enzymes and metabolic pathways. Sirtuin 3 (SIRT3) is a prominent deacetylase that participates in mitochondrial metabolism, redox balance, and mitochondrial dynamics by regulating mitochondrial protein acetylation, thereby protecting mitochondria from damage. Normal mitochondrial function is essential for maintaining the metabolism and function of the heart. Therefore, mitochondrial dysfunction caused by SIRT3 consumption and defects leads to the development of a variety of cardiovascular diseases. A comprehensive understanding of the role of SIRT3 in cardiovascular disease is critical for developing new therapeutic strategies. Herein, we summarize the function of SIRT3 in mitochondria, the complex mechanisms mediating cardiovascular diseases, and the potential value of SIRT3 small-molecule agonists in future clinical treatments.