Angiotensin II signals cardiovascular disease through metalloproteinases including MMP-2, MMP-7 and ADAM-17/TACE. We hypothesized that these metalloproteinases regulate each other at the transcriptional level. Further, MMP-2, being a major gelatinase in cardiac and vascular tissue, could mediate angiotensin II-induced cardiovascular disease. We studied the development of hypertension (by tail cuff plethysmography), cardiac hypertrophy (by M-mode echocardiography and qRT-PCR analysis of hypertrophy marker genes) and fibrosis (by collagen staining and qRT-PCR analysis of fibrosis marker genes) in mice receiving angiotensin II. Angiotensin II induced hypertension, cardiac hypertrophy and fibrosis which correlated with an upregulation of MMP-2. Downregulation of MMP-2 by pharmacological inhibition and RNA interference attenuated hypertension but not cardiac hypertrophy or fibrosis. Downregulation of MMP-7 or ADAM-17/TACE by RNA interference attenuated angiotensin II-induced MMP-2 upregulation as well as hypertension, cardiac hypertrophy and fibrosis. We conclude that MMP-2 selectively mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and ADAM-17/TACE.

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AimsHSPA12B is a newly discovered and endothelial-cell-specifically expressed heat shock protein. We have reported recently that overexpression of HSPA12B increased endothelial nitric oxide synthase (eNOS) expression in mouse cardiac tissues during endotoxemia. Endothelial NOS has been shown to protect heart from ischaemic injury. We hypothesized that overexpression of HSPA12B will attenuate cardiac dysfunction and remodelling after myocardial infarction (MI) through an eNOS-dependant mechanism.Methods and resultsMI was induced by permanent ligation of the left anterior descending coronary artery in the transgenic mice (Tg) overexpressing hspa12b gene and its wild-type (WT) littermates. Echocardiographic analysis revealed that Tg mice exhibited improvements in cardiac dysfunction and remodelling at 1 and 4 weeks after MI. These improvements were accompanied by a significant decrease in cardiomyocyte apoptosis and increase in capillary and arteriolar densities. Significant up-regulation of eNOS, VEGF, Ang-1, and Bcl-2 was also observed in Tg hearts compared with WT hearts after MI. However, pharmacological inhibition of eNOS abolished the HSPA12B-induced decrease in cardiomyocyte apoptosis and increase in capillary formation after MI. Most importantly, inhibition of eNOS abrogated the protection of HSPA12B against cardiac dysfunction and remodelling after MI.ConclusionsThese data demonstrate for the first time that the overexpression of HSPA12B attenuates cardiac dysfunction and remodelling after MI. This action of HSPA12B was mediated, at least in part, by prevention of cardiomyocyte apoptosis and promotion of myocardial angiogenesis via an eNOS-dependent mechanism. HSPA12B could be a novel target for the management of patients with post-MI cardiac dysfunction and remodelling.

AimsHSPA12B is a newly discovered and endothelial-cell-specifically expressed heat shock protein. We have reported recently that overexpression of HSPA12B increased endothelial nitric oxide synthase (eNOS) expression in mouse cardiac tissues during endotoxemia. Endothelial NOS has been shown to protect heart from ischaemic injury. We hypothesized that overexpression of HSPA12B will attenuate cardiac dysfunction and remodelling after myocardial infarction (MI) through an eNOS-dependant mechanism.Methods and resultsMI was induced by permanent ligation of the left anterior descending coronary artery in the transgenic mice (Tg) overexpressing hspa12b gene and its wild-type (WT) littermates. Echocardiographic analysis revealed that Tg mice exhibited improvements in cardiac dysfunction and remodelling at 1 and 4 weeks after MI. These improvements were accompanied by a significant decrease in cardiomyocyte apoptosis and increase in capillary and arteriolar densities. Significant up-regulation of eNOS, VEGF, Ang-1, and Bcl-2 was also observed in Tg hearts compared with WT hearts after MI. However, pharmacological inhibition of eNOS abolished the HSPA12B-induced decrease in cardiomyocyte apoptosis and increase in capillary formation after MI. Most importantly, inhibition of eNOS abrogated the protection of HSPA12B against cardiac dysfunction and remodelling after MI.ConclusionsThese data demonstrate for the first time that the overexpression of HSPA12B attenuates cardiac dysfunction and remodelling after MI. This action of HSPA12B was mediated, at least in part, by prevention of cardiomyocyte apoptosis and promotion of myocardial angiogenesis via an eNOS-dependent mechanism. HSPA12B could be a novel target for the management of patients with post-MI cardiac dysfunction and remodelling.

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Abstract Heart failure (HF) and aortic valve stenosis (AS) are complex disorders affected by functional alterations and actively regulated remodelling of the heart and the aortic valve, respectively. In addition to structural proteins, such as collagens and elastin, the extracellular matrix (ECM) in the heart and the aortic valve comprises non-collagenous factors that are not strictly involved in the architecture but may modulate cardiac and valvular remodelling. In the present study the expression of non-collagenous fibrosis- and calcification-related ECM proteins was investigated in HF-associated cardiac remodelling from different origins as well as in fibrocalcific aortic valve disease leading to AS. The experimental models of pressure overload, myocardial infarction (MI) and chronic renal failure were used to study the cardiac expression of bone morphogenetic protein (BMP)-2, BMP-4, bone sialoprotein, matrix Gla protein (MGP), osteoactivin, osteopontin, periostin and/or pleiotrophin in vivo in cardiac remodelling. Human aortic valves, obtained from patients undergoing valve replacement, were studied to characterize the valvular expression of BMP-2, BMP-4, bone sialoprotein, MGP, osteoactivin, osteopontin, osteoprotegerin, periostin, pleiotrophin, and thrombospondins (TSPs) 1-4 in the different stages of fibrocalcific aortic valve disease. Left ventricular (LV) MGP expression was upregulated in vivo in non-uremic cardiac remodelling. In vitro results indicate that angiotensin II elevates MGP expression in cardiomyocytes and fibroblasts. Periostin gene expression was induced in cardiac but not in aortic valve remodelling and the cardiac induction in chronic renal insufficiency was associated with LV hypertrophy and blood pressure as well as the cardiac gene expression of other fibrosis-related genes. Bone sialoprotein and osteopontin were expressed in the aortic valves in parallel with calcification, and also in distinct models of cardiac remodelling. Osteoprotegerin protein expression in stenotic valves was weak regardless of a simultaneous increase in gene expression. BMPs were downregulated in AS and no change in LV gene expression was detected in uremic cardiac remodelling. All the studied TSPs were expressed in human aortic valves, and especially the expression of TSP-2 was shown to increase in fibrocalcific aortic valves simultaneously with decreased activation of the Akt/nuclear factor (NF)-κB-pathway. This study delineates distinct expression patterns of non-collagenous ECM proteins in pathological tissue remodelling in the heart and in the aortic valve, and thus emphasizes the role of ECM proteins as an important modulator of cardiac and aortic valve remodelling. / Tiivistelmä Sydämen vajaatoiminnan ja aorttastenoosin taudinkuvaan kuuluvat toiminnallisten muutosten ohella aktiivisesti säädellyt soluväliaineen muutokset sydämen ja aorttaläpän rakenteessa. Soluväliaineen rakenteen muodostavien kollageenien ja elastiinin lisäksi soluväliaineessa on rakenteeseen kuulumattomia proteiineja. Tässä väitöskirjassa tutkittiin sidekudoksen kertymiseen ja kudosten kalkkiutumiseen osallistuvia soluväliaineen proteiineja sydämen vajaatoiminnassa sekä aorttastenoosiin johtavassa kalkkiuttavassa aorttaläppäviassa. Tutkimuksessa selvitettiin sydämen soluväliaineen proteiinien ilmentymistä painekuormituksen, sydäninfarktin ja pitkäaikaisen munuaisten vajaatoiminnan koemalleissa rotalla. Tutkittavia proteiineja olivat luun morfogeneettiset proteiinit 2 ja 4, luun sialoproteiini, matriksin Gla proteiini (MGP), osteoaktiviini, osteopontiini, periostiini ja pleiotropiini. Edellä mainittujen proteiinien lisäksi osteoprotegeriinin ja trombospondiinien 1-4 ilmentymistä tutkittiin kalkkiuttavan aorttaläppävian eri kehitysvaiheissa. Aorttaläpät oli kerätty tekoläppäleikkauspotilailta. Sydämessä MGP:n ilmentyminen lisääntyi kaikissa muissa paitsi munuaisten vajaatoiminnan koemallissa. Angiotensiini II nosti MGP:n ilmentymistä sydänlihassoluissa ja sidekudossoluissa. Periostiinin ilmentyminen lisääntyi sydämen uudelleenmuovautumisessa, muttei aorttaläppäviassa. Lisäksi munuaisten vajaatoiminnan aiheuttama periostiinin ilmentymisen muutos sydämessä liittyi sekä sydämen kasvuun, verenpaineen nousuun että muiden sidekudosta muokkaavien proteiinien ilmentymiseen. Luun sialoproteiinin ja osteopontiinin ilmentymiset erosivat toisistaan erilaisissa sydämen vajaatoiminnan malleissa, mutta aorttaläpissä niiden molempien ilmentyminen oli suhteessa läpän kalkkiutumiseen. Osteoprotegeriinin geenin ilmentyminen lisääntyi kalkkiutuneissa aorttaläpissä vaikkakin proteiinin määrä pysyi vähäisenä. Luun morfogeneettisten proteiinien ilmentyminen oli alentunut sairaissa läpissä, muttei sydämessä munuaisten vajaatoiminnan aikana. Aorttaläpissä ilmennettiin kaikkia trombospondiineita, joista trombospondiini-2:n ilmentyminen kasvoi sairaissa aorttaläpissä. Kalkkiutuneissa läpissä solunsisäinen Akt/NF-κB–signaalinvälitysjärjestelmä oli vaimentunut. Tutkimus osoittaa, että soluväliaineen proteiinien ilmentymistä säädellään eri tavoin sydämen vajaatoiminnassa ja aorttastenoosissa kudoksen uudelleenmuovautumisprosessin aikana.

Advancements in clinical care have led to a growing cohort of preterm-born individuals now entering adulthood. Before birth, such adults were often exposed to a suboptimal intrauterine environment, and after delivery, key developmental stages that would normally occur in utero during the third trimester had to take place under ex utero physiological conditions. Through detailed cardiovascular phenotyping, this thesis investigates the cardiovascular changes in preterm-born young adults, utilising a cohort of individuals with data collection since recruitment at birth. The detailed perinatal information was first used to design nested case-control studies to investigate the effects of early lipid and glucocorticoid exposure on long-term cardiovascular physiology in individuals born preterm. It was demonstrated that intravenous lipid administration leads to an artificial elevation of total cholesterol levels in immediate postnatal life, which is associated with long-term changes in aortic and left ventricular function proportional to the degree of cholesterol elevation. Additionally, exposure to antenatal glucocorticoids relates to a regional increase in aortic arch stiffness in young adulthood, as well as changes in glucose metabolism. It was then shown that young adults born preterm have increased left ventricular mass, out of proportion to blood pressure, and a unique three-dimensional left ventricular geometry, with reduced systolic and diastolic function compared to term-born controls. Similarly, they also show distinct differences in the right ventricle, with increased right ventricular mass and a proportion having clinically impaired right ventricular systolic function. Finally, it was demonstrated that preterm-born individuals have increased circulating levels of antiangiogenic factors in young adulthood, which relate to capillary rarefaction and blood pressure elevation. These findings are of considerable public health relevance given that nearly 10% of births are now preterm. Understanding whether modification of these variations in cardiovascular structure and function prevent the development of cardiovascular disease in this growing subgroup of the population will be of future interest.