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

响应于压力超负荷或缺血的心脏重塑不仅涉及心肌细胞改变，而且涉及成纤维细胞活化为肌成纤维细胞和过度胶原积聚，从而导致心脏功能受损。这些变化受到机械力和神经体液因素的调节。这些因子包括心房和B型钠尿肽（ANP和BNP，主要由肌细胞释放）以及C型NP（CNP，由内皮细胞和浸润性炎症细胞分泌）。NP通过特异性跨膜鸟苷酸环化酶（GC）受体和作为第二信使的环GMP（即GC A（ANP和BNP共有的受体）和GC B（CNP））进行信号传导。我们之前在遗传小鼠模型中的实验研究表明，ANP和BNP可能在心脏重塑过程中作为关键的局部抗肥大和促血管生成因子。CNP的心脏作用尚不清楚。其GC B受体在所有驻留心肌细胞（成纤维细胞、心肌细胞和血管细胞）中表达。给予合成CNP可大大减轻实验性压力超负荷或缺血小鼠的心脏肥大、纤维化和收缩功能障碍。值得注意的是，我们正在进行的心肌细胞限制性缺失GC B的新型遗传小鼠模型的研究表明，心肌细胞仅部分参与这些保护性CNP作用。在体外，合成的NP（CNP多于ANP）反调节TGF对成纤维细胞增殖、分化和胶原分泌的刺激作用。为了剖析内源性局部NP在体内的成纤维细胞作用，在这里，我们在成年小鼠中产生了诱导的成纤维细胞特异性缺失GC A或GC B的新的遗传模型，用于研究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.