Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling

Abstract

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.

Current Understanding of the Role of Nesfatin-1

“…Peripheral nesfatin-1 exerts pronounced effects on the cardiovascular system, namely an increase in blood pressure after IP administration in mice [ 139 ] and rats [ 140 ] or IV injection in rats [ 141 ], with inhibited relaxation of peripheral blood vessels probably contributing to this effect [ 141 ]. This effect is likely associated with stimulated signaling of the phosphoinositide-3-kinase (PI3K)/AKT/ m -TOR pathway and phosphorylation of Janus kinase 2 (JAK2)/STAT3, resulting in proliferation, migration, and phenotype switch of vascular smooth muscle cells from a contractile to a synthetic state by elevating the mRNA and protein expression of matrix metalloproteinase 2 and 9 while reducing peroxisome proliferator-activated receptor-γ [ 142 , 143 ]. Because NUCB2 mRNA expression was increased in the media of the aorta of spontaneously hypertensive rats [ 142 ], nesfatin-1 might play a pathogenetic role under these conditions.…”

“…This effect is likely associated with stimulated signaling of the phosphoinositide-3-kinase (PI3K)/AKT/ m -TOR pathway and phosphorylation of Janus kinase 2 (JAK2)/STAT3, resulting in proliferation, migration, and phenotype switch of vascular smooth muscle cells from a contractile to a synthetic state by elevating the mRNA and protein expression of matrix metalloproteinase 2 and 9 while reducing peroxisome proliferator-activated receptor-γ [ 142 , 143 ]. Because NUCB2 mRNA expression was increased in the media of the aorta of spontaneously hypertensive rats [ 142 ], nesfatin-1 might play a pathogenetic role under these conditions. In line with this assumption, circulating NUCB2/nesfatin-1 levels were higher in patients with essential hypertension than in normotensive controls and correlated with systolic blood pressure [ 144 ]; therefore, nesfatin-1 has been suggested as a risk factor for obesity-associated hypertension (OR 1.5) [ 145 ].…”

Avβ3 Single-Stranded DNA Aptamer Attenuates Vascular Smooth Muscle Cell Proliferation and Migration via Ras-PI3K/MAPK Pathway

“…MAPK signaling is closely related to cell growth and proliferation [35]. Lu et al showed that nesfatin-1 promoted the proliferation and migration of VSMCs by enhancing the activity of PI3K/ AKT/mTOR [36]. Vaspin inhibited high glucose-induced proliferation and migration of VSMCs induced by inhibiting MAPK and PI3K/AKT signaling [37].…”

Comparative Transcriptomic Analysis Revealed Novel Potential Therapeutic Targets Of Traditional Chinese Medicine (Pinggan-Qianyang Decoction) On Vascular Remodeling In Spontaneously Hypertensive Rats

“…The effect of mTOR inhibition and de ciency on vascular remodeling differs in physiological and pathological status [47]. The PI3K signaling pathway and its major downstream effector protein kinase B (PKB/Akt) are involved in glucose metabolism, differentiation, proliferation, apoptosis, cell migration and in ammatory responses [48,49]. Many diseases, including diabetes, atherosclerosis, hypertension, and cancers, are associated with abnormal loss or activation of the PI3K/Akt pathway [50].…”