Role of protein kinase C, PI3 kinase, tyrosine kinases, NO-synthase, K-ATP channels and MPT pore in the signaling pathway of the cardioprotective effect of chronic continuous hypoxia
GENERAL PHYSIOLOGY AND BIOPHYSICS
Authors: Tsibulnikov, Sergey Y.; Maslov, Leonid N.; Naryzhnaya, Natalia, V; Ma, Huijie; Lishmanov, Yury B.; Oeltgen, Peter R.; Garlid, Keith
Abstract
It was established that adaptation to chronic continuous normobaric hypoxia (CCNH) increases cardiac tolerance to ischemia and reperfusion. Coronary artery occlusion (20 min) and reperfusion (3 h) was performed in Wistar rats. CCNH promoted a decrease in the infarct size/area at risk ratio in 2-fold. CCNH promoted an increase in the nitrite/nitrate levels in blood serum and myocardium. Pretreatment with protein kinase C (PKC) inhibitor chelerythrine, NO-synthase (NOS) inhibitor L-NAME, iNOS inhibitor S-methylisothiourea, K-ATP channel blocker glibenclamide, mitoK(ATP) channel blocker 5-hydroxydecanoic acid abolished the infarct-reducing effect of CCNH. The non-selective tyrosine kinase inhibitor genistein attenuated but not eliminated infarct-sparing effect of CCNH. The nNOS inhibitor 7-nitroindazole, sarcK(ATP) channel blocker HMR 1098, MPT pore inhibitor atractyloside, PI3 kinase inhibitor wortmannin did not reverse infarct-limiting effect of CCNH. It was concluded that infarct-reducing effect of CCNH is mediated via PKC, iNOS activation and mitoK(ATP) channel opening. While nNOS, PI3 kinase, sarcK(ATP) channel, MPT pore are not involved in the development of CCNH-induced cardiac tolerance to impact of ischemia-reperfusion.
Genomic and phenotypic delineation of congenital microcephaly
GENETICS IN MEDICINE
Authors: Shaheen, Ranad; Alkuraya, Fowzan S.; Maddirevula, Sateesh; Ewida, Nour; Alsahli, Saud; Abdel-Salam, Ghada M. H.; Zaki, Maha S.; Al Tala, Saeed; Alhashem, Amal; Softah, Ameen; Al-Owain, Mohammed; Alazami, Anas M.; Abadel, Basma; Patel, Nisha; Al-Sheddi, Tarfa; Alomar, Rana; Alobeid, Eman; Ibrahim, Niema; Hashem, Mais; Abdulwahab, Firdous; Hamad, Muddathir; Tabarki, Brahim; Alwadei, Ali H.; Alhazzani, Fahad; Bashiri, Fahad A.; Kentab, Amal; Sahinturk, Serdar; Sherr, Elliott; Fregeau, Brieana; Sogati, Samira; Alshahwan, Saad Ali M.; Alkhalifi, Salwa; Alhumaidi, Zainab; Temtamy, Samia; Aglan, Mona; Otaify, Ghada; Girisha, Katta M.; Tulbah, Maha; Seidahmed, Mohammed Zain; Salih, Mustafa A.; Abouelhoda, Mohamed; Momin, Afaque A.; Al Saffar, Muna; Partlow, Jennifer N.; Arold, Stefan T.; Faqeih, Eissa; Walsh, Christopher
Abstract
Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.
COA
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