Abstract
Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.
Highlights
Hypertension, a threat to human health, is a complex disease that can cause end organ damage associated with vascular remodeling, which is characterized by growth, apoptosis, inflammation, and fibrosis [1]
To directly test the effect, we examined the effect of calcium-sensing receptor (CaSR) on the blood pressure levels in spontaneous hypertensive rats (SHRs), including the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP)
We demonstrated that CaSR and NLRP3 inflammasome were activated in the aortas from SHRs and vascular smooth muscle cells (VSMCs) incubated with angiotensin II (Ang II)
Summary
Hypertension, a threat to human health, is a complex disease that can cause end organ damage associated with vascular remodeling, which is characterized by growth, apoptosis, inflammation, and fibrosis [1]. Increasing evidence indicates that the inflammation and immune system activation, including proinflammatory cytokines such as interleukin (IL) and immune cells like lymphocytes, play a critical role in cardiovascular diseases, vascular injury, and VSMC phenotypic modulation and dysfunction [3, 4]. The NLRP3 inflammasome, a key signaling platform that activates highly proinflammatory cytokines, IL-1β and IL-18, contributes to the development of aortic aneurysms and hypertension via vascular inflammation [5, 6]. Activation of NLRP3 promotes the formation of the NLRP3 inflammasome complex, comprising NLRP3, apoptosis associated speck-like protein containing a caspase recruitment domain (ASC) and caspase 1 [7], which leads to cell injury and dysfunction in a caspase 1-dependent manner [6, 8]. The activation mechanisms of the NLRP3 inflammasome complex and its roles in aortic remodeling in hypertension are largely unknown
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