Fibroblasts intricately organize and regulate the extracellular matrix (ECM) in cardiac health and disease. Excess deposition of ECM proteins causes fibrosis, resulting in disrupted signaling conduction and contributing to the development of arrhythmias and impaired cardiac function. Fibrosis is causally involved in cardiac failure in the left ventricle (LV). Fibrosis likely occurs in right ventricle (RV) failure yet mechanisms remain unclear. Indeed, RV fibrosis is poorly understood with mechanisms often extrapolated from the LV to the RV. However, emerging data suggests that the LV and RV are distinct cardiac chambers and differ in regulation of the ECM and response to fibrotic stimuli. In the present review, we will discuss differences in ECM regulation in the healthy RV and LV. We will discuss the importance of fibrosis in the development of RV disease in pressure overload, inflammation, and aging. During this discussion, we will highlight mechanisms of fibrosis with respect to the synthesis of ECM proteins while acknowledging the importance of considering collagen breakdown. We will also discuss current knowledge of anti-fibrotic therapies in the RV and the need for additional research to help delineate the shared and distinct mechanisms of RV and LV fibrosis.
Right ventricular (RV) function is the strongest predictor of survival in age-related heart failure as well as other clinical contexts in which aging populations suffer significant morbidity and mortality. However, despite the significance of maintaining RV function with age and disease, mechanisms of RV failure remain poorly understood and no RV-directed therapies exist. The anti-diabetic drug and AMP-activated protein kinase (AMPK) activator metformin protects against left ventricular dysfunction, suggesting cardioprotective properties may translate to the RV. Here, we aimed to understand the impact of advanced age on pulmonary hypertension induced right ventricular dysfunction. We further aimed to test whether metformin is cardioprotective in the RV and if the protection afforded by metformin requires cardiac AMPK. We used a murine model of PH by exposing adult (4-6 months) and aged (18 months) male and female mice to hypobaric hypoxia (HH) for 4 weeks. Cardiopulmonary remodeling was exacerbated in aged mice compared to adult as evidenced by elevated RV weight and impaired RV systolic function. Metformin attenuated HH induced RV dysfunction but only in adult male mice. Metformin still protected the adult male RV even in the absence of cardiac AMPK. Together, we suggest that aging exacerbates PH-induced RV remodeling and that metformin may represent a therapeutic option for this disease in a sex and age-dependent, but in an AMPK independent manner. Ongoing efforts are aimed at elucidating the molecular basis for RV remodeling as well as delineating the mechanisms of cardioprotection provided by metformin in the absence of cardiac AMPK.
Right ventricular (RV) dysfunction dictates survival in aged‐related left –heart failure and pulmonary hypertension (PH), yet RV remodeling is poorly understood and no RV directed therapies exist. Our group previously reported that metformin, an AMP‐activated protein kinase (AMPK) activator, protects against PH‐induced RV dysfunction, yet the mechanisms of metformin‐mediated protection are unclear. The objective of this study was to elucidate the role of cardiac AMPK in PH‐RV dysfunction and whether AMPK is required for the cardioprotective effects of metformin. We used Cre‐Lox recombination techniques to delete AMPKα2 temporally and selectively from cardiomyocytes before placing male and female AMPK deleted (KO) and wild type (WT) C57Bl6 mice in a hypobaric hypoxia (HH) chamber (~17,000ft) for 4 weeks with and without metformin (200mg/kg/day). HH exposure induced cardiopulmonary remodeling as evidenced by higher lung and RV weights as well as lower RV fractional area change, pulmonary acceleration time (PAT), stroke volume (SV) and cardiac output (CO). HH‐induced cardiopulmonary remodeling was exacerbated in males compared to females, consistent with previous reports of sex differences in this model. Deletion of AMPK resulted in higher RV weights normalized to TL (RV/TL) even in control conditions, with male KO AMPK mice undergoing significantly worse RV remodeling in response to HH than females. Interestingly, deletion of cardiac‐specific AMPK also impacts lung remodeling. AMPK KO male and female mice demonstrated higher lung weights than WT in control mice and AMPK KO exacerbated lung remodeling in HH. Together, we suggest that AMPK is critical in the RV and PH‐RHF. Ongoing work will determine if cardiac‐specific AMPK is required for metformin‐mediated protection in PH‐RHF.
Right ventricle (RV) dysfunction dictates survival in pulmonary hypertension (PH) and other clinical conditions. Metformin, a clinically relevant AMP activated protein kinase (AMPK) activator, has been proposed as a therapy for PH induced right heart failure (PH‐RHF) due to its well‐reported cardioprotective properties. Indeed, our group has recently shown that metformin is protective in PH‐RHF, but the mechanisms of protection in the RV remain unknown. The objective of this study was to use determine whether the protective properties of metformin require cardiac AMPK. We used Cre‐Lox recombination to create a cardiomyocyte specific AMPK deleted with temporal regulation of expression. AMPK knockout (KO) and wild type (WT) control mice were placed in a hypobaric hypoxia (HH) chamber (~17,000ft) for 4 weeks to induce PH‐RHF, with or without metformin (200mg/kg/day) in drinking water. Cardiomyocyte specific AMPK deletion exacerbated RV and LV remodeling in response to HH compared to WT, with significant sex differences evidenced by males undergoing worse remodeling than females. AMPK deletion exacerbated cardiac output and RV stroke volume compared to WT mice. Metformin rescued cardiac remodeling in male KO mice but did not attenuate remodeling in female mice. We suggest that metformin is a potential therapeutic target to attenuate maladaptive cardiac remodeling induced by PH‐RHF, but only in male mice. Metformin does not require cardiac AMPK for cardioprotection. The mechanisms by which metformin affords protection in PH‐RHF are still unclear, but may include AMPK activity in non‐myocyte cell populations. Ongoing work will elucidate the role of AMPK activation in fibroblasts as well as other systemic and cardiac mechanisms which may explain how metformin protects against PH‐RHF.
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