Fibroblast growth factor-2 regulates myocardial infarct repair: effects on cell proliferation, scar contraction, and ventricular function.

Fibroblast growth factor-2 (FGF2, bFGF) has been proposed to regulate wound healing and angiogenesis, but skin wound healing in FGF2-knockout (FGF2-KO) animals is only slightly delayed. To determine the role of FGF2 in myocardial infarct repair, we studied the evolution of left ventricular geometry, cell proliferation, matrix content, and cardiac function in mice lacking or overexpressing (FGF2-Tg) FGF2. Despite having no effect on initial infarct size, deletion of FGF2 resulted in reduced fibroblast proliferation and interstitial collagen deposition, decreased endothelial proliferation and vascular density, and decreased cardiomyocyte hypertrophy. Furthermore, FGF2-KO mice demonstrated a complete absence of scar contraction, resulting in increased final infarct size and marked increases in chamber size and infarct expansion. These deficits ultimately impaired left ventricular dP/dt compared with wild-type infarcted mice. Conversely, overexpression of FGF2 increased fibroblast proliferation and collagen deposition, accelerated endothelial proliferation, and enhanced cardiomyocyte hypertrophy after infarction. These changes curbed infarct expansion and preserved left ventricular function. Thus, FGF2 is an important regulator of cell proliferation, angiogenesis, collagen synthesis, myocyte hypertrophy, scar contraction, and, ultimately, left ventricular contractile function during infarct repair. FGF2 may be more important in healing of infarcts compared with skin wounds because of the mechanical stress under which infarcts heal.

Altered cardiovascular responses in mice lacking the M(1) muscarinic acetylcholine receptor.

Although the M(2) muscarinic acetylcholine receptor (mAChR) is the predominant functional mAChR subtype in the heart, some responses of the cardiovascular system to acetylcholine (ACh) may be mediated by other mAChR subtypes. The potential effect of M(1) mAChR on heart function was investigated using M(1) knockout (M(1)-KO) mice. In vivo cardiodynamic analysis showed that basal values of heart rate (HR), developed left ventricular pressure (DLVP), left ventricular dP/dt(max) (LV dP/dt(max)), and mean blood pressure (MBP) were similar between wild-type (WT) and M(1)-KO mice. Injection of the putative M(1)-selective agonist 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) produced an increase in LV dP/dt(max), DLVP, HR, and MBP in WT mice but did not affect hemodynamic function in the M(1)-KO mice. The stimulatory effect of McN-A-343 in WT mice was blocked by pretreatment with propranolol, indicating that stimulation of the M(1) mAChRs on sympathetic postganglionic neurons evoked release of catecholamines. Intravenous injection of ACh in both WT and M(1)-KO mice caused atrioventricular conduction block, without a significant change in the frequency of atrial depolarization, or atrial fibrillation. Immunoprecipitation and reverse transcriptase-polymerase chain reaction failed to detect the expression of M(1) mAChR in cardiac tissue from WT mice. The carbachol-induced increase of phospholipase C activity in cardiac tissues was not different between WT and M(1)-KO mice. These results demonstrate that 1) activation of M(1) mAChR subtype on sympathetic postganglionic cells results in catecholamine-mediated cardiac stimulation, 2) M(1) mAChR is not expressed in mouse heart, and 3) administration of ACh to mice induces arrhythmia.