Adriana M Zimnicka

Publications (4)26.18 Total impact

• Article: Chronic Hypoxia Selectively Enhances L- and T-type Voltage-dependent Ca2+ Channel Activity in Pulmonary Artery by Upregulating Cav1.2 and Cav3.2.

  Jun Wan, Aya Yamamura, Adriana M Zimnicka, Guillaume Voiriot, Kimberly A Smith, Haiyang Tang, Ramon J Ayon, Moumita S R Choudhury, Eun A Ko, Jun Wang, Chen Wang, Ayako Makino, Jason X-J Yuan
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  ABSTRACT: Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vasoconstriction and vascular remodeling, which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca(2+) concentration [Ca(2+)]cyt is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation. Ca(2+) influx, through voltage-dependent Ca(2+) channels (VDCC), is an important pathway for the regulation of [Ca(2+)]cyt. The potential role for L- and T-type VDCC in HPH is still unclear. Using a HPH mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated, and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 weeks, and high K(+)- and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high K(+)- and U-46619-induced Ca(2+) influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high K(+)- and U-46619-induced contraction of mesenteric artery. Compared with MA, PA displayed higher expression of Cav1.2 and Cav3.2 upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2.
  AJP Lung Cellular and Molecular Physiology 05/2013; · 3.66 Impact Factor
• Article: Functional Characterization of Voltage-dependent Ca2+ Channels in Mouse Pulmonary Arterial Smooth Muscle Cells: Divergent Effect of ROS.

  Eun A Ko, Jun Wan, Aya Yamamura, Adriana M Zimnicka, Hisao Yamamura, Hae Young Yoo, Haiyang Tang, Kimberly A Smith, Premanand C Sundivakkam, Amy Zeifman, Ramon J Ayon, Ayako Makino, Jason X-J Yuan
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  ABSTRACT: Electromechanical coupling via membrane depolarization-mediated activation of voltage-dependent Ca(2+) channels (VDCC) is an important mechanism in regulating pulmonary vascular tone; while mouse is an animal model often used to study pathogenic mechanisms of pulmonary vascular disease. The function of VDCC in mouse pulmonary artery (PA) smooth muscle cells (PASMC), however, has not been characterized and their functional role in reactive oxygen species (ROS)-mediated regulation of vascular function remains unclear. In this study, we characterized the electrophysiological and pharmacological properties of VDCC in PASMC and the divergent effects of ROS produced by xanthine oxidase (XO) and hypoxanthine (HX) on VDCC in PA and mesenteric artery (MA). Our data show that removal of extracellular Ca(2+) or application of nifedipine, a dihydropyridine VDCC blocker, both significantly inhibited 80 mM K(+)-mediated PA contraction. In freshly dissociated PASMC, the maximum inward Ca(2+) currents were -2.6±0.2 pA/pF at +10 mV (with a holding potential of -70 mV). Window currents were between -40 and +10 mV with a peak at -15.4 mV. Nifedipine inhibited currents with an IC50 of 0.023 µM, and 1 µM Bay K8644, a dihydropyridine VDCC agonist, increased the inward currents by 61%. XO/HX attenuated 60 mM K(+)-mediated increase in [Ca(2+)]cyt due to Ca(2+) influx through VDCC in PASMC. Exposure to XO/HX caused relaxation in PA preconstricted by 80 mM K(+), but not in aorta and MA. In contrast, H(2)O(2) inhibited high K(+)-mediated increase in [Ca(2+)](cyt) and caused relaxation in both PA and MA. Indeed, RT-PCR and Western blot analysis revealed significantly lower expression of CaV1.3 in MA compared to PA. Thus, our study characterized the properties of VDCC and demonstrates that ROS differentially regulate vascular contraction by regulating VDCC in pulmonary and systemic arteries.
  AJP Cell Physiology 02/2013; · 3.54 Impact Factor
• Article: Dihydropyridine Ca2+ Channel Blockers Increase Cytosolic [Ca2+] by Activating Ca2+-sensing Receptors in Pulmonary Arterial Smooth Muscle Cells.

  Aya Yamamura, Hisao Yamamura, Qiang Guo, Adriana M Zimnicka, Jun Wang, Eun A Ko, Kimberly A Smith, Nicole M Pohl, Shanshan Song, Amy Zeifman, Ayako Makino, Jason X J Yuan
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  ABSTRACT: Rationale: An increase in cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and pulmonary vascular remodeling. The dihydropyridine Ca(2+) channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca(2+)-sensing receptor (CaSR) was upregulated and the extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (e.g., nifedipine) increase [Ca(2+)](cyt) by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca(2+)](cyt) in IPAH-PASMC was concentration dependent with an EC(50) of 0.20 µM. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca(2+)](cyt), whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca(2+)](cyt). Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca(2+)](cyt) in IPAH-PASMC; however, the non-dihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca(2+)](cyt). Conclusions: The dihydropyridine derivatives increase [Ca(2+)](cyt) by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca(2+) channels; therefore, it is possible that use the dihydropyridine Ca(2+) channel blockers (e.g., nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.
  Circulation Research 01/2013; · 9.49 Impact Factor
• Article: Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension.

  Aya Yamamura, Qiang Guo, Hisao Yamamura, Adriana M Zimnicka, Nicole M Pohl, Kimberly A Smith, Ruby A Fernandez, Amy Zeifman, Ayako Makino, Hui Dong, Jason X-J Yuan
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  ABSTRACT: A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca(2+)](cyt) and enhanced Ca(2+) influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). We examined whether the extracellular Ca(2+)-sensing receptor (CaSR) is involved in the enhanced Ca(2+) influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. In normal PASMC superfused with Ca(2+)-free solution, addition of 2.2 mmol/L Ca(2+) to the perfusate had little effect on [Ca(2+)](cyt). In IPAH-PASMC, however, restoration of extracellular Ca(2+) induced a significant increase in [Ca(2+)](cyt). Extracellular application of spermine also markedly raised [Ca(2+)](cyt) in IPAH-PASMC but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca(2+)-induced [Ca(2+)](cyt) rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH-PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca(2+)-mediated [Ca(2+)](cyt) increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. The extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca(2+) influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension.
  Circulation Research 06/2012; 111(4):469-81. · 9.49 Impact Factor