en ER-KO male mice undergoing I/R and WT was observed. Having said that, the female ER-KO mice exhibited less functional recovery immediately after I/R than WT female [64]. On the contrary, isolated Langendorff hearts from ER-KO female mice exhibited I/R injury equivalent to that observed in WT females [65]. Studies in ER-KO mice suggest that this receptor plays a relevant part within the protection observed within the female heart. Indeed, isolated Langendorff hearts from ER-KO female mice exhibited substantially much less functional recovery than WT female mice and were equivalent to WT male mice [65,66]. These ex-vivo benefits were corroborated by in vivo research. At 8 weeks soon after permanent MI, ER-KO ovariectomized (OVX) female mice showed improved mortality and larger expression of pro-atrial natriuretic peptide (ANP) in left ventricle and in serum when compared with WT mice [67]. In line, at two weeks following MI induced by left anterior descending (LAD) coronary artery CYP1 Inhibitor Accession ligation, estrogen therapy resulted in elevated Calcium Channel Inhibitor manufacturer infarct size in ER-KO OVX mice respect to ER-KO and WT OVX mice [68]. One particular possible mechanism of cardioprotection associated with ER is definitely the anti-apoptotic action. Indeed, ER-KO female mice undergoing MI had affected myocardial PI3K and Akt activation, which was associated with enhanced expression of caspase-3 and -8, too as decreased Bcl-2 levels compared with wild-type (WT) mice. These effects weren’t observed in ER-KO male mice [66]. Luo and colleagues [69] observed that in ER-KO, ER-KO and ER/ER-double KO female mice the infarct volume was bigger than in WT mice. Additionally, KO mice had decreased mitochondrial activity. The function of ERs was also evaluated in inducible transgenic mice with cardiomyocytespecific ERs-overexpression, producing possible to discriminate the impact of cardiac ER and ER from ERs-mediated systemic effects. In female mice ER-overexpression improved functional myocardial adaptation, decreased collagen type-I and -III gene expression and collagen deposition, and induced phosphorylation of JNK signaling pathway two weeks immediately after MI induced by permanent LAD ligation. In addition, ER-overexpression enhanced angiogenesis, lymphangiogenesis and neovascularization in the peri-infarct region of female and male mice [70]. A recent study demonstrated that enhanced neovascularization just after MI may be promoted by the activation of ER in endothelial progenitor cells (EPCs) via enhancing their homing and angiogenic capacity [71]. Relevantly, transplantation of estrogen-stimulated EPCs preserved cardiac function just after MI, but this impact disappeared in EPCs pre-conditioned together with the ER antagonist methyl-piperidino-pyrazole (MMP) [71] or derived from ER-KO mice and, to a lower extent, from ER-KO mice [72]. It has been demonstrated that transgenic ER (Tg-ER) mice have been additional protected against MI than WT mice. At 1 week soon after MI induced by coronary artery ligation, Tg-ER mice had improved cardiac function with lowered echocardiographic end diastole and end systolic posterior wall thickness, improved ejection fraction and fractional shortening. Moreover, cardiac collagen deposition and mRNA expression levels of collagen I, -SMA, and TGF- have been considerably reduced in Tg-ER than in WT mice [73]. Similarly, inducible ER-overexpression was associated with attenuated left ventricular (LV) dilatation, smaller sized enhance in heart weight, enhanced systolic and diastolic function in MI mice of each sexes at two weeks from LAD ligation. These effects had been linked with less reduction
