Hypoxia-Inducible Factor-1α in Pulmonary Arterial Smooth Muscle Cells and Hypoxia-induced Pulmonary Hypertension

摘要: It is imperative that organisms sense and respond to changes in oxygen concentration for their survival. Hypoxia-inducible factor-1 (HIF-1) the highly conserved global master regulator of homeostasis, genes regulated at transcriptional level by HIF-1 are involved a multitude processes, including angiogenesis, vascular reactivity remodeling, vasomotor control, glucose energy metabolism, erythropoiesis, cell proliferation viability (1). In lung, elevated levels associated with poor prognosis lung cancer (2), stabilization hypoxia-induced reactive species derived from mitochondria has been shown contribute pulmonary fibrosis patients acute injury (3–5). Chronic exposure alveolar hypoxia results sustained vasoconstriction remodeling leading development progression hypertension (HPH). Patients variety chronic diseases, such as obstructive disease, cystic fibrosis, bronchopulmonary dysplasia, idiopathic well residents living high altitude experience persistent hypoxia. This leads hypertension, which there few clinical treatments available. may eventually develop right ventricular hypertrophy heart failure death. Therefore, understanding molecular mechanisms underlying HPH critical improvement therapeutic strategies. In this issue Journal, Ball colleagues (pp. 314–324) demonstrate role HIF-1α using smooth muscle–specific conditional knockout (HIF-1α-SMM-Cre) mouse (6). The authors identify two important concepts study. First, show systolic pressure (RVSP) HIF-1α-SMM-Cre mice exposed significantly less than RVSP hypoxic control mice. These arterial muscle cells (PASMC) contributes increased induced consistent previous studies HIF-1α+/− deficiency delays comparison wild-type littermates (7, 8). indicate attenuation be due decreased response PASMC, required capacitance, membrane depolarization, K+ current density, enhanced store-operated Ca2+ entry, up-regulated canonical transient receptor potential 1 (TRPC1) TRPC6 expression, augmented Na+/H+ exchanger expression 9, 10). A rise cytosolic free ([Ca2+]cyt) PASMC major trigger an stimulus migration, remodeling. One possible explanation hypoxia, causes depolarization up-regulates channel (Figure 1). Whereas have used models general (or association ) HIF-1α, study identifies specifically HPH. Figure 1. Proposed hypoxia-inducible factor-1α (HIF-1α) failure. Hypoxia (PASMC), ... The second finding although deletion SMC attenuates increase RVSP, it does not attenuate suggests something other overload HPH. data report demonstrating insufficient explain (11). likely that, addition its many known effects, direct cardiomyocytes Overexpression cardiomyopathy contractile dysfunction resulting reduced sarco(endo)plasmic reticulum Ca2+-ATPase (12). Additionally, induces via pathogenic cardiac (13, 14). There several suggest cardioprotective effects ischemic preconditioning, where short periods ischemia reperfusion increases protects against further damage upon longer episodes stress (15). However, constitutive metabolic preconditioning increasing gene metabolism beneficial initially; however, (16). The highlights HPH, reveals necessarily correlate would interesting determine if similar concept can applied forms initial unknown. more needed multiple affects function. effect on direct, or result coronary arteries cardiomyocytes. indicates factors afterload (e.g. and/or sensitive proteins). provide better order cardiac-specific therapies treatment