• 1 Xu SQ, Yang YZ, Zhou J, et al. A mitochondrial genome sequence of the Tibetan antelope (Pantholops hodgsonii). Genomics Proteomics Bioinformatics 2005; 3:517.

    • Search Google Scholar
    • Export Citation
  • 2 Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 1999; 341:12761283.

  • 3 Russell B, Motlagh D, Ashley WW. Form follows function: how muscle shape is regulated by work. J Appl Physiol 2000; 88:11271132.

  • 4 Rhodes J, Udelson JE, Marx GR, et al. A new noninvasive method for the estimation of peak dP/dt. Circulation 1993; 88:26932699.

  • 5 Senzaki H, Paolocci N, Gluzband YA, et al. Beta-blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. Circ Res 2000; 86:807815.

    • Search Google Scholar
    • Export Citation
  • 6 Senzaki H, Isoda T, Paolocci N, et al. Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation 2000; 101:10401048.

    • Search Google Scholar
    • Export Citation
  • 7 Cornolo J, Mollard P, Brugniaux JV, et al. Autonomic control of the cardiovascular system during acclimatization to high altitude: effects of sildenafil. J Appl Physiol 2004; 97:935940.

    • Search Google Scholar
    • Export Citation
  • 8 McKinsey TA. Derepression of pathological cardiac genes by members of the CaM kinase superfamily. Cardiovasc Res 2007; 73:667677.

  • 9 Grueter CE, Colbran RJ, Anderson ME. CaMKII, an emerging molecular driver for calcium homeostasis, arrhythmias, and cardiac dysfunction. J Mol Med 2007; 85:514.

    • Search Google Scholar
    • Export Citation
  • 10 Simonson TS, Yang Y, Huff CD, et al. Genetic evidence for high-altitude adaptation in Tibet. Science 2010; 329:7275.

  • 11 Braun AP, Schulman H. The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol 1995; 57:417445.

    • Search Google Scholar
    • Export Citation
  • 12 Edman CF, Schulman H. Identification and characterization of delta B-CaM kinase and delta C-CaM kinase from rat heart, two new multifunctional Ca2+/calmodulin-dependent protein kinase isoforms. Biochim Biophys Acta 1994; 1221:89101.

    • Search Google Scholar
    • Export Citation
  • 13 Tobimatsu T, Fujisawa H. Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J Biol Chem 1989; 264:1790717912.

    • Search Google Scholar
    • Export Citation
  • 14 Yuan K, Bai GY, Park WH, et al. Stimulation of ANP secretion by 2-Cl-IB-MECA through A(3) receptor and CaMKII. Peptides 2008; 29:22162224.

    • Search Google Scholar
    • Export Citation
  • 15 Zhao PJ, Pan J, Li F, et al. Effects of chronic hypoxia on the expression of calmodulin and calcicum/calmodulin-dependent protein kinase II and the calcium activity in myocardial cells in young rats. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10:381385.

    • Search Google Scholar
    • Export Citation
  • 16 Kirchhefer U, Schmitz W, Scholz H, et al. Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovasc Res 1999; 42:254261.

    • Search Google Scholar
    • Export Citation
  • 17 Ge RL, Kubo K, Kobayashi T, et al. Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude. Am J Physiol 1998; 274:H1792H1799.

    • Search Google Scholar
    • Export Citation
  • 18 Beall CM, Brittenham GM, Strohl KP, et al. Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 1998; 106:385400.

    • Search Google Scholar
    • Export Citation
  • 19 Zhang H, Wu CX, Chamba Y, et al. Blood characteristics for high altitude adaptation in Tibetan chickens. Poult Sci 2007; 86:13841389.

  • 20 Yi X, Liang Y, Huerta-Sanchez E, et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 2010; 329:7578.

  • 21 Beall CM, Cavalleri GL, Deng L, et al. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A 2010; 107:1145911464.

    • Search Google Scholar
    • Export Citation

Advertisement

Cardiac adaptive mechanisms of Tibetan antelope (Pantholops hodgsonii) at high altitudes

Chang Rong PhD1, Ma Yan MS2, Bai Zhen-Zhong PhD3, Yang Ying-Zhong PhD4, Lu Dian-Xiang PhD5, Ma Qi-sheng MD6, Ga Qing MS7, Liu Yin MD8, and Ri-Li Ge MD, PhD9
View More View Less
  • 1 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 2 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 3 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 4 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 5 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 6 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 7 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.
  • | 8 Affiliated Hospital, Qinghai University, Xining 810001, China.
  • | 9 Research Center for High Altitude Medicine, Qinghai University Medical College, Qinghai University, Xining 810001, China.

Abstract

Objective—To identify cardiac mechanisms that contribute to adaptation to high altitudes in Tibetan antelope (Pantholops hodgsonii).

Animals—9 male Tibetan antelope and 10 male Tibetan sheep (Ovis aries).

Procedures—Tibetan antelope and Tibetan sheep inhabiting a region with an altitude of 4,300 m were captured, and several cardiac variables were measured. Expression of genes for atrial natriuretic peptide, brain natriuretic peptide, and calcium-calmodulin–dependent protein kinase II δ was measured via real-time PCR assay.

Results—Ratios of heart weight to body weight for Tibetan antelope were significantly greater than those of Tibetan sheep, but ratios of right-left ventricular weights were similar. Mean ± SD baseline heart rate (26.33 ± 6.15 beats/min) and systolic arterial blood pressure (97.75 ± 9.56 mm Hg) of antelope were significantly lower than those of sheep (34.20 ± 6.57 beats/min and 130.06 ± 17.79 mm Hg, respectively). The maximum rate of rise in ventricular pressure in antelope was similar to that in Tibetan sheep, but after exposure to air providing a fraction of inspired oxygen of 14.6% or 12.5% (ie, hypoxic conditions), the maximum rate of rise in ventricular pressure of the antelope increased significantly to 145.1% or 148.1%, respectively, whereas that of the sheep decreased to 68.4% or 70.5%, respectively. Gene expression of calcium-calmodulin–dependent protein kinase II δ and atrial natriuretic peptide, but not brain natriuretic peptide, in the left ventricle of the heart was significantly higher in antelope than in sheep.

Conclusions and Clinical Relevance—Hearts of the Tibetan antelope in this study were well adapted to high-altitude hypoxia as shown by higher heart weight ratios, cardiac contractility in hypoxic conditions, and expression of key genes regulating cardiac contractility and cardiac hypertrophy, compared with values for Tibetan sheep.

Contributor Notes

Supported by grants from the National Basic Research Program of China (No. 2012CB518200), Program of International S&T Cooperation of China (No. 2011PFA32720), and National Natural Science Foundation of China (No. 31160219).

Address correspondence to Dr. Ge (geriligao@hotmail.com).