Different effects of fenoldopam and angiotensin II on autophagy in vascular smooth muscle cells

Abstract

Both dopamine and angiotensin II are essential neurotransmitters/hormones with pleiotropic functions in vascular smooth muscle cells (VSMCs). Autophagy, an intracellular self-degradative process that delivers cytoplasmic constituents to lysosomes, plays an important role in physiological homeostasis in VSMCs. Fenoldopam (Fen), a dopamine D 1 /D 5 receptor agonist, increases autophagic flux in renal proximal tubule cells, however, in VSMCs the roles of these two neurotransmitters on autophagy are unknown. In rat aortic VSMCs, Fen increased autophagy, determined by the protein expression of microtubule-associated protein 1 light chain (LC)3-II and autophagy related 5 (ATG5), in a concentration- and time-dependent manner. By contrast, angiotensin II (Ang II), the endogenous AT 1 R agonist, decreased the protein expression of LC3-II and ATG5 in a concentration-and time-dependent manner. Further studies showed that Fen (1 μM, 15 min) increased while Ang II (100 nM, 15 min) decreased cyclic AMP (cAMP) production in VSMCs (Vehicle: 100±35.4%, Fen: 513.7±95.8%, Ang II: 24.6±8.0%, n=6). Pre-treatment with Rp-cAMPS (50 μM, 6 hr), a PKA inhibitor, attenuated the Fen-mediated increase in LC3-II protein expression (Fen: 1 μM, 6 hr) (Vehicle: 100±15.0%, Fen: 251.8±37.2%, Fen+Rp-cAMP: 96.9±16.7%, n=6) and reversed the Ang II-mediated decrease in autophagy (Ang II: 100 nM, 6 hr) (Vehicle: 100±8.9%, Ang II: 44.9±6.3%, Ang II+Rp-cAMP: 95.4±11.0%, n=4). These results demonstrate distinct roles of Fen and Ang II on autophagy through regulation of cAMP/PKA signaling by their corresponding receptors in VSMCs. This study was supported by National Institutes of Health of US and National Natural Science Foundation of China. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.