Chen L A, Vatner D E, Vatner S F, Hittinger L, Homcy C J
Department of Medicine, Harvard Medical School, Massachusetts General Hospital 02114.
J Clin Invest. 1991 Jan;87(1):293-8. doi: 10.1172/JCI114985.
We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in Gs functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and Gs activity, as determined in the S49 cyc- reconstitution assay, were measured in sarcolemma from normal (NL), left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously, we measured the mRNA level encoding for the Gs alpha subunit. These studies indicate that Gs activity and Gs alpha mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (Gs activity, pmol cyclic AMP/10 min per microgram, NL 4.2 +/- 0.4, LVH 3.0 +/- 0.2, HF 3.2 +/- 0.3; Gs alpha mRNA, pg/10 micrograms RNA, NL 131 +/- 9.0, LVH 104 +/- 7.4, HF 97.4 +/- 9.1; P less than 0.05 as compared with NL for LVH and HF). Accompanying this decrement in Gs activity is a fall in adenylyl cyclase, both basal and stimulated. However, we also identified a further decrease in adenylyl cyclase without any additional change in Gs or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g., NaF-stimulated activity, pmol cyclic AMP/min per mg, NL 420.2 +/- 17.5, LVH 347.1 +/- 29.6, HF 244.2 +/- 27.3; P less than 0.05 compared with NL for LVH and HF, P less than 0.05 compared with LVH for HF). In summary, these studies indicate that both Gs and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase, independent of Gs, in the setting of heart failure.
我们之前报道过，压力超负荷诱导的肥大和心力衰竭动物的心肌肌膜中，腺苷酸环化酶存在整体减少，同时Gs功能活性降低。本研究旨在确定单纯的肥大（无心力衰竭）是否足以促使这些变化发生，以及心力衰竭的叠加是否会加剧这些变化。通过S49 cyc-重组试验测定正常（NL）、左心室肥大（LVH）和心力衰竭（HF）动物的心肌肌膜中基础和刺激状态下的腺苷酸环化酶及Gs活性。同时，我们测量了编码Gsα亚基的mRNA水平。这些研究表明，在心力衰竭的心脏以及心力衰竭发生前代偿性肥大的心脏中，Gs活性和Gsα mRNA均下降约30%（Gs活性，pmol环磷酸腺苷/10分钟/微克，NL 4.2±0.4，LVH 3.0±0.2，HF 3.2±0.3；Gsα mRNA，pg/10微克RNA，NL 131±9.0，LVH 104±7.4，HF 97.4±9.1；与NL相比，LVH和HF的P均小于0.05）。伴随Gs活性的这种降低，基础和刺激状态下的腺苷酸环化酶均下降。然而，我们还发现，与代偿性LV肥大的动物相比，心力衰竭动物的心肌肌膜中腺苷酸环化酶进一步降低，而Gs或其α亚基mRNA水平无任何额外变化（例如，NaF刺激的活性，pmol环磷酸腺苷/分钟/毫克，NL 420.2±17.5，LVH 347.1±29.6，HF 244.2±27.3；与NL相比，LVH和HF的P均小于0.05，与LVH相比，HF的P小于0.05）。总之，这些研究表明，Gs和腺苷酸环化酶活性均随着LV肥大的发展而平行下降，随后在心力衰竭情况下，腺苷酸环化酶进一步降低，且与Gs无关。
