Local, fibroblast-specific cardiac actions of the natriuretic peptides ANP, BNP and CNP

压力超负荷或缺血引起的心脏重塑不仅涉及心肌细胞的改变，而且还涉及成纤维细胞向肌成纤维细胞的激活和过度的胶原堆积，从而导致心功能受损。这些变化受机械力和神经体液因素的调节。这些因子包括心钠素和B型(ANP和BNP，主要由心肌细胞释放)以及C型NP(CNP，由内皮细胞和浸润性炎症细胞分泌)。NPS信号通过特异性跨膜鸟苷酸环化酶(GC)受体和环GMP作为第二信使，即GCAA(ANP和BNP共有的受体)和GC B(CNP)。我们先前在遗传小鼠模型上的实验研究表明，ANP和BNP可能是心脏重塑过程中关键的局部抗肥厚和促血管生成因子。CNP的心脏作用还不是很清楚。它的GC B受体在所有常驻心肌细胞(成纤维细胞、心肌细胞和血管细胞)中都有表达。给予人工合成的CNP可显著减轻实验性压力超负荷或缺血小鼠的心肌肥大、纤维化和收缩功能障碍。值得注意的是，我们正在进行的具有心肌细胞限制性GC B缺失的新的遗传小鼠模型的研究表明，心肌细胞只部分参与了这些保护CNP的作用。在体外，人工合成的纳米粒(CNP多于ANP)可以逆转转化生长因子对成纤维细胞增殖、分化和胶原分泌的刺激作用。为了剖析体内内源性局部NPs的成纤维细胞作用，我们在成年小鼠中建立了诱导成纤维细胞特异性缺失GC A或GC B的新遗传模型，以研究其对高血压或缺血性心脏病的影响。

Cardiac remodeling in response to pressure overload or ischemia involves not only cardiomyocyte alterations but also activation of fibroblasts to myofibroblasts and excessive collagen accumulation contributing to impaired cardiac function. These changes are modulated by mechanical forces and neurohumoral factors. Among these factors are the natriuretic peptides atrial and B type (ANP and BNP, mainly released from myocytes) as well as C type NP (CNP, secreted by endothelial and infiltrating inflammatory cells). NPs signal through specific transmembrane guanylyl cyclase (GC) receptors and cyclic GMP as second messenger, namely GC A (the receptor shared by ANP and BNP) and GC B (for CNP). Our previous experimental studies in genetic mouse models showed that ANP and BNP may act as key local antihypertrophic and proangiogenic factors during cardiac remodeling. The cardiac role of CNP is less well understood. Its GC B receptor is expressed in all resident myocardial cells (fibroblasts, cardiomyocytes and vascular cells). Administration of synthetic CNP greatly attenuates cardiac hypertrophy, fibrosis and contractile dysfunction in mice with experimental pressure overload or ischemia. Notably, our ongoing studies of a novel genetic mouse model with cardiomyocyte restricted deletion of GC B indicate that myocytes are only partly involved in these protective CNP actions. In vitro, synthetic NPs (CNP more than ANP) counterregulate the stimulatory effects of TGF on fibroblast proliferation, differentiation and collagen secretion. To dissect the fibroblast actions of endogenous local NPs in vivo, here we generate new genetic models with induced, fibroblast specific deletion of either GC A or GC B in adult mice for studies of the impact on hypertensive or ischemic heart disease.