Smad1 Protects Cardiomyocytes From Ischemia-Reperfusion Injury

Abstract

Background-We previously reported that bone morphogenetic protein 2 (BMP2) protected against apoptosis of serum-deprived cardiomyocytes via induction of Bcl-xL through the Smad1 pathway. To investigate whether Smad1 signaling promotes cell survival in the adult heart, we subjected transgenic mice with cardiac-specific overexpression of smad1 gene (Smad1TG) to ischemia-reperfusion (I/R) injury. Methods and Results-The effects of BMP2 or adenovirus-mediated transfection of smad1 on cardiomyocyte survival in hypoxia-reoxygenation were examined using rat neonatal cardiomyocytes. BMP2 and Smad1 each significantly promoted survival and diminished apoptotic death of cardiomyocytes during hypoxia-reoxygenation. Interestingly, Smad1 was found to be activated during I/R in normal mouse heart. To examine physiological and pathological roles of Smad1 in I/R, we generated Smad1TG using the ␣-myosin heavy chain gene promoter. Phosphorylation of Smad1 was found in all smad1 transgene-positive mouse hearts. To examine whether Smad1 prevents injury of cardiomyocytes in vivo, we subjected Smad1TG and age-matched wild-type mice (WT) to I/R injury induced by 1 hour of ligation of the left coronary artery and 1 hour of reperfusion. TUNEL and DNA ladder analyses showed that Smad1TG had significantly smaller myocardial infarctions and fewer apoptotic deaths of cardiomyocytes than did WT. Interestingly, increased expression of Bcl-xL and ␤-catenin was more remarkable whereas caspase3 was less activated in Smad1TG heart than in that of WT. Conclusions-These findings suggest that the Smad1 signaling pathway plays a role in cardioprotection against I/R injury.

Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts

“…Loss of GSK3β in mice leads to β-catenin stabilization and increased cardiomyocyte proliferation during development, while conditional loss of GSK3β in adult cardiomyocytes leads to increased cardiomyocyte proliferation after injury [10,45]. Likewise, Smad1 overexpression in adult mouse hearts protects cardiomyocytes from I/R injury and also induces β-catenin protein expression [46]. Current studies are directed towards determining if Tbx20-overexpressing cardiomyocytes are induced to proliferate or are resistant to cell death with cardiac injury.…”

Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP)

“…In a CHIP depletion mouse model, a severe phenotype of early death was observed, as the mouse suffered from an inability of degradation of misfolded proteins and dysfunction of the quality control machinery (43). The role of CHIP in maximal myocardial protection was reported (44), whereas Smad1 also showed a role in protection of cardiomyocytes from ischemiareperfusion injury (45). However, the physiological relevance in heart disease remains unclear as CHIP regulates degradation of FIGURE 6.…”

Bone morphogenetic protein-2 acts upstream of myocyte-specific enhancer factor 2a to control embryonic cardiac contractility☆

“…Isolation and culture of neonatal rat ventricular cardiomyocytes, adult rat ventricular cardiomyocytes and embryonic rat cardiac myocyte Ventricular cardiomyocytes were isolated from the hearts of 1-day-old Sprague Dawley rats or adult rats as described previously [21,[24][25][26]. Rat cardiomyocytes were purified from embryonic day 15 (E15) embryos as described previously [25,27].…”

“…The neonatal rat cardiomyocyte model is conducive to a broad spectrum of experiments, such as studies of contraction, ischaemia, hypoxia and the toxicity of various compounds [20,21].…”