Download or read book Calcium Signaling Pathways in Smooth Muscle Remodeling During Hypertension and Asthma written by Martin Johnson and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Hypertension and asthma are highly prevalent and debilitating diseases. A common feature that has been recognized as pathogenic for these two diseases is the remodeling of the vasculature and airways. Specifically, the thickening of the smooth muscle layers of the vasculature and airways is critical for these disease processes. At the cellular level, smooth muscle cells dedifferentiate from a healthy contractile/quiescent phenotype to a highly proliferative, migratory, and secretory phenotype during vascular and airway remodeling. This phenotypic switch is also accompanied by a molecular reprogramming of the calcium (Ca2+) signaling machinery. Numerous ion channels and transporters are modulated in this dedifferentiation to favor a repertoire that spatiotemporally disseminates Ca2+ signals that activate fibroproliferative signaling at the expense of contractile function. One Ca2+ signaling pathway that reprograms during vascular and airway remodeling is the store-operated Ca2+ entry (SOCE) pathway. SOCE is initiated by depletion of the endoplasmic reticulum (ER) Ca2+ stores by receptor agonists. Upon depletion, the ER transmembrane protein, STIM, activates the plasma membrane (PM) ORAI Ca2+ channel. The activation of SOCE stimulates fibroproliferative pathways. Although not carefully studied in smooth muscle cells, the novel mitochondrial sodium (Na+)/Ca2+/Lithium (Li+) Exchanger (NCLX) has also emerged as essential for migration and proliferation for other cell types. NCLX mediates Ca2+ extrusion from the mitochondria. This dissertation illuminates how STIM1 and NCLX have critical roles in mediating smooth muscle remodeling in hypertension and asthma. We first identified L-type Ca2+ channel blockers (LCCBs), which are common antihypertensive drugs, to activate the N-terminus of STIM and stimulate vascular smooth muscle remodeling. Clinical use of LCCBs was also correlated with adverse outcomes of vascular remodeling (i.e., heart failure). In another study, we showed that STIM1 protein expression is enhanced in asthmatic airway smooth muscle (ASM). Furthermore, STIM1 was necessary for airway remodeling in asthma by stimulating pro-remodeling transcriptional reprogramming, enhancing metabolism, and activating the nuclear factor of activated T cells 4 (NFAT4) isoform. STIM1 was also crucial for airway hyperresponsiveness (AHR), possibly as a result of reduced airway remodeling (AR) and agonist-induced Ca2+ oscillations in ASM. In our final study, we further validated that NCLX regulates SOCE in ASM. Moreover, NCLX, like STIM1, is critical for regulating AR and AHR in asthma. However, NCLX mediates AR by activating pro-remodeling transcriptional reprogramming, modulation of metabolism, and the activation of Ca2+/calmodulin-dependent kinase II (CaMKII). Thus, these three critical studies further elucidate the molecular reprogramming that occurs during smooth muscle remodeling in hypertension and asthma. Furthermore, they suggest STIM and NCLX may be novel molecular targets for these diseases.