A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8.
A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8.
复制标题
DOI：
10.7554/elife.80949
复制
发表时间：
2022-12-14
期刊：
影响因子：
7.7
通讯作者：
Lakatta EG
中科院分区：
文献类型：
--
作者：
Tarasov KV;Chakir K;Riordon DR;Lyashkov AE;Ahmet I;Perino MG;Silvester AJ;Zhang J;Wang M;Lukyanenko YO;Qu JH;Barrera MC;Juhaszova M;Tarasova YS;Ziman B;Telljohann R;Kumar V;Ranek M;Lammons J;Bychkov R;de Cabo R;Jun S;Keceli G;Gupta A;Yang D;Aon MA;Adamo L;Morrell CH;Otu W;Carroll C;Chambers S;Paolocci N;Huynh T;Pacak K;Weiss R;Field L;Sollott SJ;Lakatta EG
心脏特异性过表达腺苷酸环化酶（AC）VIII型（TGAC 8）的成年（3个月）小鼠适应cAMP诱导的心脏工作负荷增加（心率、射血分数和心输出量增加约30%）长达一年，没有心力衰竭或过度死亡的迹象。在这里，我们显示在TGAC 8中不存在经典的心脏肥大标记物，并且总左心室（LV）质量没有增加：与野生型（WT）同窝仔相比，TGAC 8中减少的LV腔体积被更厚的LV壁包裹，所述LV壁包含增加数量的小心肌细胞和小间质增殖非心肌细胞的网络;与WT相比，TGAC 8中的蛋白质合成、蛋白体活性和自噬增强，并且Nrf-2、Hsp 90 α和ACC 2蛋白水平增加。尽管增加的能量需求，在体内LV ATP和磷酸肌酸水平在TGAC 8没有从WT不同。无偏组学分析鉴定了超过2，000种转录物和蛋白质，包括跨多个细胞区室的广泛生物过程，其因基因型而不同;与WT相比，在TGAC 8中，在戊糖磷酸分流和核苷酸合成的利用增加的背景下，存在从脂肪酸氧化到有氧糖酵解的转变。因此，AC 8的显著过表达参与了在哺乳动物细胞中进化的复杂、协调的适应“回路”，以防御威胁健康或生命的应激（其要素已经被证明是心脏缺血预调节和运动耐力心脏调节的核心），其可能具有生物学意义以允许疾病状态（例如心肌梗塞或心力衰竭）的适当愈合。
Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.